Antimicrobial agents

ABSTRACT

The invention provides a compound of formula (I): or a salt or prodrug thereof, wherein R 1 , R 4 -R 8 , R 10 , R 2′ -R 6′ , W, and A have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as antibacterial agents.

PRIORITY OF INVENTION

This application is a 371 PCT/US11/39839 filed Jun. 9, 2001, which claims priority to United States Provisional Application No. 61/353,107, filed 9 Jun. 2010; 61/355,408, filed 16 Jun. 2010; 61/372,770, filed 11 Aug. 2010; and 61/372,755, filed 11 Aug. 2010.

BACKGROUND OF THE INVENTION

The emergence of Multidrug Resistant (MDR) bacterial pathogens (e.g. methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii-calcoaceticus complex (ABC), etc.) has increased concerns as to the adequacy of current antimicrobials and pathogen treatment methods. The lethality of such pathogens, particularly MRSA, has often led to treatment methods that are experimental or would otherwise normally be avoided in standard clinical practice. For example, the antibiotic colistin was traditionally considered too nephrotoxic and neurotoxic for clinical use, but is nevertheless used to treat many MDR bacterial infections due to a paucity of available active drugs. The growing threat from MDR pathogens highlights a critical need to expand currently available antimicrobials. In this connection, there is a pressing need for new antibiotics that exhibit novel mechanisms of action or that are able to circumvent known resistance pathways.

Elements of the bacterial cell division machinery present appealing targets for antimicrobial compounds because (i) they are essential for bacterial viability, (ii) they are widely conserved among bacterial pathogens, and (iii) they often have markedly different structures than their eukaryotic homologs. One such protein that has been identified as a potential target is the FtsZ protein. During the division process, FtsZ, along with approximately 15 other proteins, assemble at mid-cell into a large cell division complex (termed the divisome), ultimately facilitating cell cytokinesis. More importantly, FtsZ is widely conserved among many bacterial strains.

SUMMARY OF THE INVENTION

In one embodiment the invention provides compounds that display antimicrobial activity. Accordingly, the invention provides a compound of formula I:

-   wherein R¹, R⁴-R⁸, R¹⁰, R²′-R⁶′, W, and A have the values defined in     a), b), and c) below: -   a) when the dashed line - - - is a single bond, R¹⁰ is present, then     W is NR⁹ or (NR⁹R^(a))⁺X⁻ and R⁹ and R⁶′ taken together are —(CR¹³     ₂)₂— or —CR¹⁴═CR¹⁴—; or

when the dashed line - - - is a single bond, R¹⁰ is present, then W is NR^(b) or (NR^(c)R^(d))⁺X⁻;

when the dashed line - - - is a double bond, and R¹⁰ is absent, then W is (NR⁹)⁺X⁻ and R⁹ and R⁶′ taken together are —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or

when the dashed line - - - is a double bond, and R¹⁹ is absent, then W is N or (NR^(a))⁺X⁻; or

when the dashed line - - - is a single bond, R¹ is R²⁰, and R¹¹, then W is NR⁹ or (NR⁹R^(a))⁺X⁻ and R⁹ and R⁶′ taken together are —(CR¹³ ₂)₂—; or

when the dashed line - - - is a single bond, R¹ is R²⁰, and R¹⁰ is R¹¹, then W is NR^(b) or (NR^(c)R^(d))⁺X⁻;

when the dashed line - - - is a single bond, R¹ is R²¹, and R¹⁰ is R¹¹, then W is NR⁹ or (NR⁹R^(a))⁺X⁻ and R⁹ and R⁶′ taken together are —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or

when the dashed line - - - is a single bond, R¹ is R²¹, and R¹⁰ is R¹¹, then W is NR^(b) or (NR^(c)R^(d))⁺X⁻;

X⁻ is a counterion;

A is N or CR⁴′;

R¹ is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryloxy or arylthio; and R¹⁰ is H or (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and (C₁-C₆)alkylthio of R¹ and R¹⁰ is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f), and wherein any aryloxy, or arylthio of R¹ and R¹⁰ is optionally substituted with one or more groups selected from halo, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f); or R¹ and R¹⁰ together with the carbon to which they are attached form a carbonyl group;

at least one of R⁴, R⁵, R²′, and R³′ is aryl substituted with one or more R^(cc) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); or at least one of R⁴, R⁵, R²′, and R³′ is aryl substituted with one or more (C₁-C₆)alkoxy and optionally substituted with one or more R^(ee); or at least one of R⁴, R⁵, R²′, and R³′ is heteroaryl substituted with one or more R^(dd) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); or at least one of R⁴, R⁵, R²′, and R³′ is aryl(C₁-C₆)alkoxy; and the remainder of R⁴, R⁵, R²′, and R³′ are each independently selected from hydrogen, halo, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy, heteroaryl(C₁-C₆)alkoxy, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R²′, and R³′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R²′, and R³′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(aa), —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h);

any adjacent R⁶, R⁷, R⁸, R⁴′, and R⁵′ taken together can optionally be methylenedioxy and each remaining R⁶, R⁷, R⁸, R⁴′, and R⁵′ is independently selected from H, R^(bb), and B—R^(x);

each B is independently selected from —O—, —S—, and —N(R^(y))—;

R⁶′ is H, alkyl, halo, —NR^(e)R^(f), NO₂, aryl, heteroaryl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl or heteroaryl(C₁-C₆)alkanoyl wherein alkyl, aryl, heteroaryl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl or heteroaryl(C₁-C₆)alkanoyl are optionally substituted with one or more groups selected from halo, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

each R¹³ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryloxy or arylthio wherein any (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and (C₁-C₆)alkylthio of R¹³ is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f), and wherein any aryloxy, or arylthio of R¹³ is optionally substituted with one or more groups selected from halo, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

each R¹⁴ is independently H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, aryloxy or arylthio wherein any (C₁-C₆)alkyl, (C₁-C₆)alkoxy, and (C₁-C₆)alkylthio of R¹⁴ is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f), and wherein any aryloxy, or arylthio of R¹⁴ is optionally substituted with one or more groups selected from halo, cyano, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R²⁰ is —NR^(gg)R^(gh) and R¹¹ is H or (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl, of R¹¹ is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R²¹ is —NR^(he)—C(═NR^(hb))—NR^(hc)R^(hd), —C(═NR^(hb))—NR^(hc)R^(hd), —NR^(ke)—C(═NR^(kb))R^(ke), or —NR^(ke)—C(═O)—NR^(kc)R^(kd), and R¹¹ is H or (C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl, of R¹¹ is optionally substituted with one or more groups selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R^(a) is (C₁-C₆)alkyl wherein (C₁-C₆)alkyl is optionally substituted with one or more groups independently selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R^(b) is H or (C₁-C₆)alkyl wherein (C₁-C₆)alkyl is optionally substituted with one or more groups independently selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R^(c) and R^(d) are each independently selected from (C₁-C₆)alkyl wherein (C₁-C₆)alkyl is optionally substituted with one or more groups independently selected from halo, cyano, oxo (═O), (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, carboxy, NO₂, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyloxy, aryl, heteroaryl, aryloxy, heteroaryloxy, and —NR^(e)R^(f);

R^(e) and R^(f) are each independently H, (C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆) alkyl; or R^(e) and R^(f) together with the nitrogen to which they are attached form a morpholino, piperazino, pyrrolidino or piperidino;

each R^(g) and R^(h) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(g) and R^(h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(j) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(k) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(u) and R^(v) is independently selected from H and (C₁-C₆)alkyl;

each R^(x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(u)R^(v);

each R^(y) is independently selected from H and (C₁-C₆)alkyl;

each R^(aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); and

and

each R^(bb) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h);

each R^(cc) is independently selected from a) aryl that is substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); b) heteroaryl that is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); or c) aryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkoxy; and

each R^(dd) is independently aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h);

each R^(ee) is independently aryl that is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h);

each R^(gg) and R^(gh) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(g) and R^(h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(hb) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(hc) and R^(hd) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(hc) and R^(hd) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(hc) and R^(hd) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(hm)R^(hn);

each R^(he) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(hm) and R^(hn) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(hm) and R^(hn) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(kb) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(kc) and R^(kd) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(kc) and R^(kd) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(kc) and R^(kd) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(km)R^(kn);

each R^(ke) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and

each R^(km) and R^(kn) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(km) and R^(kn) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; or

-   b) the bond represented by - - - is present, R¹⁰ is absent, and W is     (NR³⁰)⁺D⁻ except as defined below when R³⁰ and R^(3a) taken together     with the atoms to which they are attached form a 5- or 6-membered     heterocyclic ring or a 5- or 6-membered heteroaromatic ring;

R¹ is —NR^(3a)R^(3b), —C(═NR^(3cb))—NR^(3cc)R^(3cd), aryloxy, cyano, or (C₁-C₆)alkyl that is substituted with one or more —NR3^(ce)—C(═NR^(3cb))R^(3ce), —C(═NR^(3cb))—NR^(3cc)R^(3cd), —NR^(3ce)—C(═NR^(3cb))—NR^(3cc)R^(3cd), and —NR^(3ce)—C(═O)—NR^(3cc)R^(3cd);

at least one of R⁴, R⁵, R²′, R³′, and R⁶′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; and the remainder of R⁴, R⁵, R²′, R³′, and R⁶′ are independently selected from hydrogen, halo, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

any adjacent R⁶, R⁷, R⁸, R⁴′ and R⁵′ taken together can optionally be methylenedioxy and each remaining R⁶, R⁷, R⁸, R⁴′ and R⁵′ is independently selected from H, R^(3bb), and Z—R^(3x);

each Z is independently selected from —O—, —S—, and —N(R^(3y))—;

R³⁰ is absent and is absent; or R³⁰ is H or (C₁-C₆)alkyl and D⁻ is counterion;

or R³⁰ and R^(3a) taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring, wherein a) when the bond represented by - - - is present in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰)⁺D⁻ and D⁻ is a counterion, b) when the bond represented by - - - is absent in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰R³¹)⁺D⁻R³¹ is (C₁-C₆)alkyl and IT is a counterion, or c) when the bond represented by - - - is absent in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰);

A is N or C—R⁴′;

R^(3a) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, —NR^(3da)R^(3db), and aryloxy, and wherein each aryl and heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; and R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═NR^(3cb))—NR^(3cc)R^(3cd), —C(═NR^(3cb))—R^(3ea), —C(═O)—R^(3m), —C(═O)—OR^(3n), —C(═O)—SR^(3p), —C(═O)—NR^(3q)R^(3r), —C(═S)—R^(3m), —C(═S)—OR^(3n), —C(═S)—SR^(3p), or —C(═S)—NR^(3q)R^(3r); wherein each (C₁-C₆)alkyl of R^(3b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, —NR^(3da)R^(3db), and aryloxy; and wherein each aryl, and heteroaryl of R^(b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; or R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino, pyrrole, indole, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino pyrrole, indole, or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl;

R^(3c) is hydrogen, (C₁-C₆)alkyl, aryl, or heteroaryl;

R^(3d) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(3e)R^(3f);

R^(3e) and R^(3f) are each independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3e) and R^(3f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3g) and R^(3h) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3g) and R^(3h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3j) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3k) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3m) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3n) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

each R^(3p) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

each R^(3q) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(3r) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3q) and R^(3r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3u) and R^(3v) is independently selected from H and (C₁-C₆)alkyl;

each R^(3x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(3u)R^(3v);

each R^(3y) is independently selected from H and (C₁-C₆)alkyl;

each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and

each R^(3bb) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

each R^(3cb) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3cc) and R^(3cd) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3cc) and R^(3cd) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(3cc) and R^(3cd) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(3cm)R^(3cn);

each R^(3ce) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3cg) and R^(3ch) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3cg) and R^(3ch) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(3cg) and R^(3ch) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(3cm)R^(3cn);

each R^(3cm) and R^(3cn) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(cm) and R^(cn) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3da) and R^(3db) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3da) and R^(3db) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

R^(ea) is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, or (C₁-C₆)alkanoyl;

or

c) when the dashed line - - - is a double bond, and R¹⁰ is absent, then W is (NR⁴¹)⁺W⁻ and R⁴¹ and R⁶′ taken together are —CHR⁴³—CHR⁴²—, or —CR⁴³—CR⁴²—;

R¹ is —NR^(4a)R^(4b), —C(═NR^(4cb))—NR^(4cc)R^(4cd), cyano, or (C₁-C₆)alkyl that is substituted with one or more —NR^(4ce)—C(═NR^(4cb))R^(4ce); —C(═NR^(4cb))—NR^(4cc)R^(4cd); and —NR^(4ce)—C(═NR^(4cb))—NR^(4cc)R^(4cd);

R⁴′, R⁵′, R⁶, R⁷ and R⁸ are each indepentyl selected from H and Z—R^(x); or R⁴′ and R⁵′ taken together are methylenedioxy and R⁶, R⁷, and R⁸ are each indepentyl selected from H and Z—R^(x); or R⁸ and 7 taken together are methylenedioxy and R⁴′, R⁵′, and R⁶ are each indepentyl selected from H and Z—R^(x); or R⁷ and R⁶ taken together are methylenedioxy and R⁴′, R⁵′, and R⁸ are each indepentyl selected from H and —Z—R^(4x);

each Z is independently selected from —O—, —S—, and —N(R^(4y))—;

at least one of R²′, R³′, R⁴, and R⁵ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; and the remainder of R²′, R³′, R⁴, and R⁵ are independently selected from H, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, and (C₁-C₆)alkanoyl of R²′, R³′, R⁴, and R⁵ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), and —NR^(4g)R^(4h); and wherein each aryl and heteroaryl of R²′, R³′, R⁴, and R⁵ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), R^(4s), and —NR^(4g)R^(4h);

R⁴² is H, (C₁-C₆)alkyl, aryl, heteroaryl, or aryl(C₁-C₆)alkyl;

R⁴³ is H, (C₁-C₆)alkyl, aryl, heteroaryl, or aryl(C₁-C₆)alkyl;

R^(4a) is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(4a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy, and wherein each aryl and heteroaryl of R^(4a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; and R^(4b) is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═O)—R^(4m), —C(═O)—OR^(4n), —C(═O)—SR^(4p), —C(═O)—NR^(4q)R^(4r), —C(═S)—R^(4m), —C(═S)—OR^(4n), —C(═S)—SR^(4p), —C(═S)—NR^(4q)R^(4r), or —C(═NR^(4c))—R^(4d); wherein each (C₁-C₆)alkyl of R^(4b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy; and wherein each aryl, and heteroaryl of R^(b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; or R^(4a) and R^(4b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one of more (C₁-C₆)alkyl;

R^(4c) is H, (C₁-C₆)alkyl, aryl, or heteroaryl;

R^(4d) is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(4e)R^(4f);

R^(4e) and R^(4f) are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(4e) and R^(4f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4g) and R^(4h) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(g) and R^(h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4j) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4k) is independently selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4m) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4n) is independently selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4p) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4q) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(r) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(q) and R^(r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4s) is independently trifluoromethyl, trifluoromethoxy, or aryl optionally substituted with one or more (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), trifluoromethyl, trifluoromethoxy, and —NR^(4g)R^(4h);

each R^(4u) and R^(4v) is independently selected from H and (C₁-C₆)alkyl;

each R^(4x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(4u)R^(4v);

each R^(4y) is independently selected from H and (C₁-C₆)alkyl;

each R^(4cb) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4cc) and R^(cd) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(4cc) and R^(4cd) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(4cc) and R^(4cd) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(4cm)R^(4n);

each R^(4ce) is independently selected from H, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4cg) and R^(4ch) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(4cg) and R^(4ch) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(4ch) and R^(4ch) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(4cm)R^(4cn);

each R^(4cm) and R^(4cn) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(4cm) and R^(4cn) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and

W⁻ is a counter anion;

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Ih:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Ij:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Ik:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Im:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Ip:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula Ir:

wherein Z is —(CR¹³ ₂)₂— or —CR¹⁴═CR¹⁴—; or a pharmaceutically acceptable salt or prodrug thereof.

In one specific embodiment of the invention at least one B is —O—.

In one specific embodiment of the invention at least one B is —S—.

In one specific embodiment of the invention at least one B is —N(R^(y))—.

In one specific embodiment of the invention R^(x) is (C₁-C₆)alkyl.

In one specific embodiment of the invention R¹ is cyano.

In one specific embodiment of the invention R¹ is aryloxy.

In one specific embodiment of the invention R¹ is phenoxy.

In one specific embodiment of the invention R¹ is —NR^(3a)R^(3b).

In one specific embodiment of the invention R¹ is —NR^(3a)R^(3b); R^(3a) is hydrogen or (C₁-C₆)alkyl; and R^(3b) is (C₁-C₆)alkyl that is substituted with one or more —NR^(3da)R^(3db).

In one specific embodiment of the invention R¹ is —NR^(3a)R^(3b); R^(3a) is hydrogen; and R^(3b) is (C₁-C₆)alkyl that is substituted with —NH₂.

In one specific embodiment of the invention R¹ is —NR^(3a)R^(3b); R^(3a) is hydrogen; and R^(3b) is 2-aminoethyl.

In one specific embodiment of the invention R¹ is —NR^(3a)—C(═NR^(3cb))—NR^(3cc)R^(3cd).

In one specific embodiment of the invention R¹ is —NH—C(═NH)—NH₂.

In one specific embodiment of the invention R⁸ is (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁸ is methoxy.

In one specific embodiment of the invention R⁷ is (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁷ is methoxy.

In one specific embodiment of the invention R⁶ is (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁶ is methoxy.

In one specific embodiment of the invention R⁴′ is (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁴′ is methoxy.

In one specific embodiment of the invention R⁵′ is (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁵′ is methoxy.

In one specific embodiment of the invention R⁶, R⁷, R⁸, R⁴′ and R⁵′ are each independently (C₁-C₃)alkoxy.

In one specific embodiment of the invention R⁶, R⁷, R⁸, R⁴′ and R⁵′ are each methoxy.

In one specific embodiment of the invention R⁷, R⁸, R⁴′ and R⁵′ are each methoxy.

In one specific embodiment of the invention R⁷ and R⁸ taken together are methylenedioxy.

In one specific embodiment of the invention R⁶ and R⁷ taken together are methylenedioxy.

In one specific embodiment of the invention R⁴′ and R⁵′ taken together are methylenedioxy.

In one specific embodiment of the invention R⁶ and R⁷ taken together are methylenedioxy and R⁴′ and R⁵′ taken together are methylenedioxy.

In one specific embodiment of the invention R¹ is methyl.

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′ and R³′ is aryl substituted with one or more R^(cc) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′ and R³′ is phenyl substituted with one or more R^(cc) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(cc) is aryl that is substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(cc) is heteroaryl that is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(cc) is phenyl that is substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(cc) is pyridyl or furyl that is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′ and R³′ is heteroaryl substituted with one or more R^(dd) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′ and R³′ is pyridyl or furyl substituted with one or more R^(dd) and optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′, and R³′ is aryl(C₁-C₆)alkoxy.

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′, and R³′ is benzyloxy.

In one specific embodiment of the invention each R^(dd) is independently aryl, which is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(dd) is independently heteroaryl, which is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(dd) is independently phenyl, which is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention each R^(dd) is independently pyridyl or furyl, which pyridyl or furyl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h);

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′ and R³′ is 4-(3-dimethylaminophenyl)phenyl, 2-phenyl-pyrid-5-yl, 2-(3-methoxyphenyl)pyrid-5-yl, 2-phenyl-furan-4-yl, 2-(pyrid-4-yl)pyrid-5-yl, 4-phenylpyrid-2-yl, 2,6-diphenylpyrid-4-yl, 3-phenylphenyl, or 3,5-diphenylphenyl.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) wherein:

the bond represented by - - - is present, R¹⁰ is absent, and W is (NR³⁰)⁺D⁻ except as defined below when R³⁰ and R^(3a) taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring;

R¹ is —NR^(3a)R^(3b) or cyano;

at least one of R⁴, R⁵, R²′, R³′, and R⁶′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; and the remainder of R⁴, R⁵, R²′, R³′, and R⁶′ are independently selected from hydrogen, halo, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

any adjacent R⁶, R⁷, R⁸, R⁴′ and R⁵′ taken together can optionally be methylenedioxy and each remaining R⁶, R⁷, R⁸, R⁴′ and R⁵′ is independently selected from H, R^(3bb), and Z—R^(3x);

each Z is independently selected from —O—, —S—, and —N(R^(3y))—;

R³⁰ is absent and if is absent; or R³⁰ is H or (C₁-C₆)alkyl and if is counterion;

or R³⁰ and R^(3a) taken together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring or a 5- or 6-membered heteroaromatic ring, wherein a) when the bond represented by - - - is present in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰)⁺D⁻ and D⁻ is a counterion, b) when the bond represented by - - - is absent in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰R³¹)⁺D⁻R³¹ is (C₁-C₆)alkyl and if is a counterion, or c) when the bond represented by - - - is absent in the 5- or 6-membered heterocyclic ring or the 5- or 6-membered heteroaromatic ring, then W is (NR³⁰);

A is N or C—R⁴′;

R^(3a) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, and aryloxy, and wherein each aryl and heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; and R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═O)—R^(3m), —C(═O)—OR^(3n), —C(═O)—SR^(3p), —C(═O)—NR^(3q)R^(3r), —C(═S)—R^(3m), —C(═S)—OR^(3n), —C(═S)—SR^(3p), —C(═S)—NR^(3q)R^(3r), or —C(═NR^(3c))—R^(3d); wherein each (C₁-C₆)alkyl of R^(3b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, and aryloxy; and wherein each aryl, and heteroaryl of R^(b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; or R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino, pyrrole, indole, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino pyrrole, indole, or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl;

R^(3c) is hydrogen, (C₁-C₆)alkyl, aryl, or heteroaryl;

R^(3d) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(3e)R^(3f);

R^(3e) and R^(3f) are each independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3e) and R^(3f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3g) and R^(3h) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3g) and R^(3h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3j) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3k) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3m) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3n) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

each R^(3p) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

each R^(3q) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(3r) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3r) and R^(3r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3u) and R^(3v) is independently selected from H and (C₁-C₆)alkyl;

each R^(3x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(3u)R^(3v);

each R^(3y) is independently selected from H and (C₁-C₆)alkyl;

each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and

each R^(3bb) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one embodiment the invention provides a compound of formula (I) wherein:

the bond represented by - - - is present, R¹⁰ is absent, and W is (NR³⁰)⁺D⁻;

R⁶ R⁷, R⁸, R⁴′ and R⁵′ are each indepentyl selected from H and Z—R^(x); or R⁶ and R⁷ taken together are methylenedioxy and R⁸, R⁴′, and R⁵′ are each indepentyl selected from H and Z—R^(x); or R⁷ and R⁸ taken together are methylenedioxy and R⁶, R⁴′ and R⁵′ are each indepentyl selected from H and Z—R^(x); or R⁴′ and R⁵′ taken together are methylenedioxy and R⁶, R⁷, and R⁸ are each indepentyl selected from H and —Z—R^(x);

each Z is independently selected from —O—, —S—, and —N(R^(y))—;

at least one of R⁴, R⁵, R²′, R³′, and R⁶′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; and the remainder of R⁴, R⁵, R²′, R³′, and R⁶′ are independently selected from hydrogen, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R²′, R³′, and R⁶′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h);

R³⁰ is absent and r is absent; or R³⁰ is H or (C₁-C₆)alkyl and X⁻ is counterion;

R¹¹ is —NR^(3a)R^(3b) or cyano;

R^(3a) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(3a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy, and wherein each aryl and heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; and R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═O)—R^(3m), —C(═O)—OR^(3n), —C(═O)—S3p^(p), —C(═O)—NR^(3q)R^(3r), —C(═S)—R^(3m), —C(═S)—OR^(3n), —C(═S)—SR^(3p), —C(═S)—NR^(3q)R^(3r), or —C(═NR^(3c))—R^(3d); wherein each (C₁-C₆)alkyl of R^(3b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy; and wherein each aryl, and heteroaryl of R^(3b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; or R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one of more (C₁-C₆)alkyl;

R^(3c) is hydrogen, (C₁-C₆)alkyl, aryl, or heteroaryl;

R^(3d) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(3e)R^(3f);

R^(3e) and R^(3f) are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(e) and R^(f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3g) and R^(3h) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3g) and R^(3h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3j) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3k) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3m) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3n) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3p) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(3q) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(3r) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3q) and R^(3r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(3u) and R^(3v) is independently selected from H and (C₁-C₆)alkyl;

each R^(3x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(3u)R^(3v); and

each R^(3y) is independently selected from H and (C₁-C₆)alkyl.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IIIa):

wherein R⁶′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁶′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁶′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IIIb):

wherein R³′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R³′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R³′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IIIc):

wherein R²′ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R²′ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂Rv^(k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R²′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IIId):

wherein R⁴ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁴ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IIIe):

wherein R⁵ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁵ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁵ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt or prodrug thereof.

In one specific embodiment of the invention R³⁰ is (C₁-C₆)alkyl and D⁻ is counterion.

In one specific embodiment of the invention R³⁰ is absent and D⁻ is absent.

In one specific embodiment of the invention at least one Z is —O—.

In one specific embodiment of the invention at least one Z is —S—.

In one specific embodiment of the invention at least one Z is —N(R^(3y))—.

In one specific embodiment of the invention each Z is —O—.

In one specific embodiment of the invention each Z is —S—.

In one specific embodiment of the invention each Z is —N(R^(3y))—.

In one specific embodiment of the invention R^(3x) is (C₁-C₆)alkyl.

In one specific embodiment of the invention R^(3a) is hydrogen or methyl.

In one specific embodiment of the invention R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl.

In one specific embodiment of the invention R^(3b) is hydrogen, methyl, phenyl, or benzyl.

In one specific embodiment of the invention R^(3b) is —C(═NR^(3c))—R^(3d).

In one specific embodiment of the invention R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl.

In one specific embodiment of the invention R^(3c) is hydrogen.

In one specific embodiment of the invention R^(3d) is methyl or amino.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one specific embodiment of the invention R⁶′ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R⁶′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R³′ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R³′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(aa), —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h); and each R^(aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(g)R^(h), —N(R^(j))S(O)₂R^(k), and —NR^(g)R^(h).

In one specific embodiment of the invention R²′ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R²′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂Rv^(k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁴ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R⁴ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h); —N(R^(3j))S(O)₂R^(3k); and —NR^(3g)R^(3h); each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁵ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R⁵ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —N³R^(g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁶′ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)Rv^(h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)Rv^(h).

In one specific embodiment of the invention R³′ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and NR^(3g)R^(3h).

In one specific embodiment of the invention R²′ is selected from aryl and heteroaryl, which aryl, and heteroaryl of R²′ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g3)R^(h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁴ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —^(N)(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); And each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁵ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).

In one specific embodiment of the invention R⁶′ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from phenyl, pyridyl, —NR^(3g)R^(3h), (C₁-C₆)alkoxy, dimethylaminophenyl, and halo.

In one specific embodiment of the invention R³′ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from phenyl, pyridyl, —NR^(3g)R^(3h), (C₁-C₆)alkoxy, dimethylaminophenyl, and halo.

In one specific embodiment of the invention R²′ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from phenyl, pyridyl, —NR^(3g)R^(3h), (C₁-C₆)alkoxy, dimethylaminophenyl, and halo.

In one specific embodiment of the invention R⁴ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from phenyl, pyridyl, —NR^(3g)R^(3h), (C₁-C₆)alkoxy, dimethylaminophenyl, and halo.

In one specific embodiment of the invention R⁵ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from phenyl, pyridyl, —NR^(3g)R^(3h), (C₁-C₆)alkoxy, dimethylaminophenyl, and halo.

In one specific embodiment of the invention at least one of R⁴, R⁵, R²′, R³′, and R⁶′ is selected from 3-biphenyl, 3-(4′-fluoro)biphenyl, 4-biphenyl, 4-(4′-fluoro)biphenyl, 3,5-bis(4-fluorophenyl)phenyl, 4-fluorophenyl, phenyl, 3-pyridyl, 4-pyridyl, 3-dimethylaminophenyl, 3-furanyl, 3-methoxyphenyl, 4-pyrid-3-ylphenyl, 4-pyrid-4-ylphenyl, 4-(3-dimethylaminophenypphenyl, 4-(3-furanyl)phenyl, 2-phenylpyrid-4-yl, 2-(3-methoxyphenyl)pyrid-3-yl, 2-phenylfur-4-yl, and 2-pyrid-4-yl)pyrid-5-yl.

In one specific embodiment of the invention A is N.

In one specific embodiment of the invention A is C—R⁴′.

In one embodiment the invention provides a compound of formula (I) wherein:

the dashed line - - - is a double bond, R¹⁰ is absent, W is (NR⁴¹)⁺W⁻ and R⁴¹ and R⁶′ taken together are —CHR⁴³— CHR⁴²—, or —CR⁴³═CR⁴²—;

R⁴′, R⁵′, R⁶, R⁷ and R⁸ are each indepentyl selected from H and Z—R^(4x); or R⁴′ and R⁵′ taken together are methylenedioxy and R⁶, R⁷, and R⁸ are each indepentyl selected from H and Z—R^(4x); or R⁷ and R⁸ taken together are methylenedioxy and R⁴′, R⁵′, and R⁶ are each indepentyl selected from H and Z—R^(4x); or R⁶ and R⁷ taken together are methylenedioxy and R⁴′, R⁵′, and R⁸ are each indepentyl selected from H and —Z—R^(4x);

each Z is independently selected from —O—, —S—, and —N(R^(4y))—;

at least one of R²′, R³′, R⁴, and R⁵ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; and the remainder of R²′, R³′, R⁴, and R⁵ are independently selected from H, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, and (C₁-C₆)alkanoyl of R²′, R³′, R⁴, and R⁵ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), and —NR^(4g)R^(4h); and wherein each aryl and heteroaryl of R²′, R³′, R⁴, and R⁵ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), R^(4s), and —NR^(4g)R^(4h);

R⁴² is H, (C₁-C₆)alkyl, aryl, heteroaryl, or aryl(C₁-C₆)alkyl;

R⁴³ is H, (C₁-C₆)alkyl, aryl, heteroaryl, or aryl(C₁-C₆)alkyl;

R¹ is —NR^(a)R^(b) or cyano;

R^(4a) is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy, and wherein each aryl and heteroaryl of R^(4a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; and R^(4b) is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═O)—R^(4m), —C(═O)—OR^(4n), —C(═O)—SR^(4p), —C(═O)—NR^(4q)R^(4r), —C(═S)—R^(4m), —C(═S)—OR^(4n), —C(═S)—SR^(4p), —C(═S)—NR^(4q)R^(4r), or —C(═NR^(4c))—R^(4d); wherein each (C₁-C₆)alkyl of R^(4b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy; and wherein each aryl, and heteroaryl of R^(4b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; or R^(4a) and R^(4b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl;

R^(4c) is H, (C₁-C₆)alkyl, aryl, or heteroaryl;

R^(4d) is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(e)R^(f);

R^(4e) and R^(4f) are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(4e) and R^(4f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4g) and R^(4h) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(4g) and R^(4h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4j) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4k) is independently selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4m) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4n) is independently selected from (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4p) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl;

each R^(4q) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(r) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(4q) and R^(4r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino;

each R^(4s) is independently trifluoromethyl, trifluoromethoxy, or aryl optionally substituted with one or more (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(4g)R^(4h), —N(R^(4j))S(O)₂R^(4k), trifluoromethyl, trifluoromethoxy, and —NR^(4g)R^(4h);

each R^(4u) and ⁴R^(v) is independently selected from H and (C₁-C₆)alkyl;

each R^(4x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(u)R^(v);

each R^(4y) is independently selected from H and (C₁-C₆)alkyl; and

W⁻ is a counter anion;

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVa):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVb):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVc):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVd):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVe):

or a salt or prodrug thereof. 121. The compound of claim 1 which is a compound of formula (IVf):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (IVg):

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is a compound of formula (Ih):

or a salt or prodrug thereof.

In one specific embodiment of the invention at least one Z is —N(R^(4y))—.

In one specific embodiment of the invention each Z is —N(R^(4y))—.

In one specific embodiment of the invention R^(4x) is (C₁-C₆)alkyl.

In one specific embodiment of the invention R⁴′, R⁵′, R⁶, and R⁷ are each methoxy.

In one specific embodiment of the invention R¹ is —NR^(4a)R^(4b).

In one specific embodiment of the invention R^(4a) is hydrogen or methyl.

In one specific embodiment of the invention R^(4b) is H, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl.

In one specific embodiment of the invention R^(4b) is H, methyl, phenyl, or benzyl.

In one specific embodiment of the invention R^(4b) is —C(═NR^(4c))—R^(4d).

In one specific embodiment of the invention R^(4a) and R^(4b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl.

In one specific embodiment of the invention R^(4c) is hydrogen.

In one specific embodiment of the invention R^(4d) is methyl or amino.

In one specific embodiment of the invention R⁴² and R⁴³ are each H.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

In one embodiment the invention provides a compound of formula (I) which is:

or a salt or prodrug thereof.

Generally, compounds of the invention including compounds of formula I set a), as well as synthetic intermediates that can be used for preparing compounds of formula I, can be prepared as illustrated in the following Schemes. It is understood that groups R¹-R¹², W, Y, and Z shown in the Schemes below can represent the final groups present in a corresponding compound of formula I or that these groups can represent groups that can be converted to the final groups present in a corresponding compound of formula I at a convenient point in a synthetic sequence. For example, in the Schemes below, the groups R¹-R¹², W, Y, and Z can comprise one or more protecting groups that can be removed at a convenient point in a synthetic sequence to provide the corresponding final groups in the compound of formula I.

Condensation of readily available anhydride 1 and amine 2 can furnish imide 3. The resulting imide 3 can then be hydrolyzed to the corresponding acid amide 4. Acid catalyzed cyclization of 4 can then lead to oxypseudoberbernine 5. The key intermediate compound 5 can then be converted to compound 6, 7, and 8 using conventional chemistry. Each of these compounds can then be quarternized to afford the desired compounds 9, 10, and 11 respectively.

The substituted N-Boc protected benzylamine 20 can be converted to the dilithio 21 by treatment with two equivalents of sec-butyllithium. Acylation of dianion 21 can be accomplished by treatment with N-methoxy-N-methylamides derivative 23 (made from the corresponding acid 22) to afford the key intermediate compound 24. Exposure of ketone 24 to a catalytic amount of TFA can provide the Boc-1,2-dihydroisoquinoline 25. The Boc group in 25 can be removed to provide 25a and the resulting free amine can be functionalized to 26 by various electrophilic reagents. Alternatively 26 can be converted to compound 28.

Beckmann rearrangement of α-ketooxime 29 with phosphorus pentachloride can produce 3-chloro-1(2H)isoquinolone 30 using literature methods. Suzuki coupling of 30 with boronic acid 31 can afford the key compound 32. Compound 32 can then be converted to triflate 33 which in turn can undergo a second Suzuki reaction with a boronic acid to afford compound 34. Quarternization of 34 can then lead to compound 35.

Scheme 4 illustrates methods and intermediates that are useful for preparing R³′ substituted compounds of the invention.

Scheme 5 illustrates the synthesis carried out in Example 1 hereinbelow.

Scheme 6 illustrates methods and intermediates that are useful for preparing R⁴ substituted compounds of the invention.

Scheme 7 illustrates methods and intermediates that are useful for preparing compounds that are substituted at R⁴ and R³′.

Scheme 8 illustrates the preparation of an intermediate phenethylamine that is useful for preparing compounds of the invention.

Scheme 8a illustrates methods for the preparation of phenethylamine intermediates that have R¹⁴ substituents. The formation of β-substituted derivatives uses a nucleophile in a Michael addition reaction and the α-substituted derivatives is formed from a carbanion generated at the position adjacent to the nitro substituent, followed by reaction with an appropriate electrophile.

Scheme 9 illustrates methods and intermediates that are useful for preparing compounds of the invention.

Scheme 10 illustrates methods and intermediates that are useful for preparing R⁷ substituted compounds of the invention.

Scheme 11 illustrates the preparation of isoquinoline intermediates that are useful for preparing compounds of the invention.

Scheme 12 illustrates the preparation of a triflate intermediate that is useful for preparing compounds of the invention.

Scheme 13 illustrates methods and intermediates that are useful for preparing R³′ substituted compounds of this invention.

Scheme 14 illustrates methods and intermediates that are useful for preparing R²′ substituted compounds of the invention.

Scheme 15 illustrates methods and intermediates that are useful for preparing R³′ substituted compounds of the invention.

Scheme 16 illustrates methods and intermediates that are useful for preparing R³′ substituted compounds of the invention.

Scheme 17 illustrates methods and intermediates that are useful for preparing R²′ substituted compounds of the invention.

Scheme 18 illustrates methods and intermediates that are useful for preparing R⁵ substituted compounds of the invention.

Compounds of formula I wherein R²′ is other than hydrogen can be prepared as illustrated in Scheme 19.

Scheme 33 illustrates how intermediate chloro compound 3 can be used for preparing compounds of formula I.

Scheme 34 illustrates how intermediate chloro compounds 4 and 5 can be preparing.

Scheme 35 illustrates the preparation of a representative compound of the invention wherein R³⁰ and R^(3a) taken together with the atoms to which they are attached form a ring.

Scheme 36 illustrates the preparation of a representative compound of the invention wherein R³⁰ and R^(3a) taken together with the atoms to which they are attached form a ring.

Scheme 37 illustrates a method for the preparation of various 2-substituted 8-oxo-5,6-dihydro-3,10,11-trimethoxydibenzo[a,g]quinolizines that are useful intermediates for preparing compounds of formula I using appropriately substituted phenethylamines and 2-bromobenzoic acids.

Scheme 38 illustrates a method for the preparation of various 2-substituted 8-oxo-5,6-dihydro-3-methoxy-9,10-dimethylenedibenzo[a,g]quinolizines that are useful intermediates for preparing compounds of formula I using appropriately substituted phenethylamines and 2-bromobenzoic acids.

Scheme 39 illustrates a general method for the preparation of various 2-substituted-8-amino-5,6-dihydro-3,10,11-trimethoxydibenzo[a,g]quinolizium and 2-substituted-8-cyano-5,6-dihydro-3,10,11-trimethoxydibenzo[a,g]quinolizium compounds of formula I.

Scheme 40 illustrates the preparation of various 8-oxo-5,6-dihydro-dibenzo[a,g]quinolizines using appropriately substituted isoquinolin-1-ones and 1-bromo-2-(2-bromoethyl)benzene intermediates.

Scheme 41 illustrates the preparation of various 8-oxo-5,6-dihydro-dibenzo[a,g]quinolizines using appropriately substituted isoquinolines and 1-bromo-2-(2-bromoethyl)benzen derivatives. The 8-oxo-5,6-dihydrodibenzo[a,g]quinolizine intermediates are useful intermediates for preparing compounds of formula I.

Scheme 42 illustrates general methods for preparing 8-oxo-5,6-dihydrodibenzo[a,g]-quinolizines that are useful for preparing compounds of formula I.

Scheme 43 illustrates methods for preparing 8-oxo-5,6-dihydrodibenzo[a,g]quinolizines that are useful for preparing compounds of formula I.

Scheme 44 illustrates a ring-closing metathesis method for preparing 8-oxo-dibenzo[a,g]quinolizine intermediates and their 5,6-dihydro analogs. These compounds are useful intermediates for preparing compounds of formula I.

Scheme 45 illustrates a method for preparing varied R² substituents of 8-oxo-dibenzo[a,g]quinolizines and 5,6-dihydro-8-oxo-dibenzo[a,g]quinolizines that can be converted into the corresponding 8-chloro dibenzo[a,g]quinolizinium compounds.

Scheme 46 illustrates a method for preparing varied R² substituents of 8-oxo-dibenzo[a,g]quinolizines and 5,6-dihydro-8-oxo-dibenzo[a,g]quinolizines that can be converted into the corresponding 8-chloro dibenzo[a,g]quinolizinium compounds.

Scheme 47 illustrates a method for preparing 8-oxo-dibenzo[a,g]quinolizines and 5,6-dihydro-8-oxo-dibenzo[a,g]quinolizines using an intramolecular Wittig-Horner reaction.

Scheme 48 illustrates a method for preparing 8-oxo-dibenzo[a,g]quinolizines and 5,6-dihydro-8-oxo-dibenzo[a,g]quinolizines that can ultimately be converted into the corresponding 8-chlorodibenzo[a,g]quinolizinium compounds.

By binding to FtsZ, the compounds of the present invention inhibit the ability of the protein to hydrolyze GTP. This inhibition of FtsZ GTPase activity, in turn, inhibits the ability of the protein to polymerize into Z-rings, as Z-ring formation requires GTP hydrolysis as an energy source for driving the reaction. Since the Z-ring serves as the scaffold for recruitment of all other proteins that comprise the divisome complex, inhibition of Z-ring formation by the compounds of the present invention also results in a corresponding inhibition of divisome protein recruitment.

The compounds of the invention are useful to treat bacterial infections including infections by Gram-negative bacterial strains, Gram-positive bacterial strains and multiple drug-resistant bacterial strains

Gram-negative bacterial strains include Escherchia coli, Caulobacter crescentus, Pseudomonas aeruginosa, Agrobacterium tumefaciens, Branhamella catarrhalis, Citrobacter diversus, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Enterobacter asburiae, Pantoea agglomerans, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis, Proteus mirabilis, Salmonella typhimurium, Salmonella enteriditis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter lwofli, Fusobacterium nucleatum, Veillonella parvula, Bacteroides forsythus, Actinobacillus actinomycetemcomitans, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Helicobacter pylori, Francisella tularensis, Yersinia pestis, Borrelia burgdorferi, Neisseria meningitidis and Haemophilus influenza.

Gram-positive bacterial strains include Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, Streptococcus faecalis, Enterococcus faecalis, Enterococcus faecium, Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Micrococcus luteus, Mycobacterium tuberculosis, Clostridium difficile, Propionibacterium acnes, Streptococcus mutans, Actinomyces viscosus, Actinomyces naeslundii, Streptococcus sanguis, Streptococcus pneumoniae, Streptococcus viridans and Streptococcus salivarius.

Multiple drug-resistant bacterial strains include methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, multiple drug-resistant Mycobacterium tuberculosis, multidrug-resistant Clostridium difficile.

In one embodiment compounds of the present invention may be administered as a composition used to treat and/or prevent a bacterial infection wherein the bacterial cell uses polymerized FtsZ protein, or a homolog thereof, to facilitate cytokinesis. To this end, compounds of the present invention may be administered to treat Staph Infections, Tuberculosis, Urinary Tract Infections, Meningitis, Enteric Infections, Wound Infections, Acne, Encephalitis, Skin Ulcers, Bed Sores, Gastric and Duodenal Ulcers, Eczema, Periodontal disease, Gingivitis, Halitosis, Anthrax, Tularemia, Endocarditis, Prostatitis, Osteomyelitis, Lyme Disease, Pneumonia, or the like.

The compositions can, if desired, also contain other active therapeutic agents, such as a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an anti-cancer, other antimicrobial (for example, an aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, a cephalosporin, a fluororquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an anti-psoriatic, a corticosteriod, an anabolic steroid, a diabetes-related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium-related hormone, an antidiarrheal, an anti-tussive, an anti-emetic, an anti-ulcer, a laxative, an anticoagulant, an erythropieitin (for example, epoetin alpha), a filgrastim (for example, G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (for example, basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator, a mydriatic, a cycloplegic, an alkylating agent, an anti-metabolite, a mitotic inhibitor, a radiopharmaceutical, an anti-depressant, an anti-manic agent, an anti-psychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog thereof, dornase alpha (Pulmozyme), a cytokine, or any combination thereof.

The term “prodrug” as used herein refers to any compound that when administered to a biological system (e.g. a mammal such as a human) generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s) or by some other process. A prodrug is thus a modified (e.g. covalently modified) analog or latent form of a therapeutically-active compound. A prodrug may also be an active metabolite or therapeutically-active compound itself.

By way of example a prodrug may generate the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191; Tranoyl-Opalinski, I., Fernandes, A., Thomas, M., Gesson, J.-P., and Papot, S., Anti-Cancer Agents in Med. Chem., 8 (2008) 618-637). Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the invention include, but are not limited to nitroreductase, proteases (e.g. serine proteases such as prostate specific antigen (PSA), amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording the corresponding anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

Pharmaceutically suitable counterions include pharmaceutically suitable cations and pharmaceutically suitable anions that are well known in the art. Examples of pharmaceutically suitable anions include, but are not limited to those described above (e.g. physiologically acceptable anions) including Cl⁻, Br⁻, I⁻, CH₃SO₃ ⁻, CF₃SO₃ ⁻, p-CH₃C₆H₄SO₃ ⁻, citrate, tartrate, malate, fumarate, formate, or acetate.

It will be appreciated by those skilled in the art that a compound of the invention comprising a counterion can be converted to a compound of the invention comprising a different counterion. Such a conversion can be accomplished using a variety of well known techniques and materials including but not limited to ion exchange resins, ion exchange chromatography and selective crystallization.

The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluents, excipient or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 90% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations, particles, and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, nanoparticles, and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about 0.1 to about 500 mg/kg, e.g., from about 0.5 to about 400 mg/kg of body weight per day, such as 1 to about 250 mg per kilogram body weight of the recipient per day.

The compound is conveniently formulated in unit dosage form; for example, containing 0.5 to 500 mg, 1 to 400 mg, or 0.5 to 100 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

The ability of a compound of the invention to alter the polymerization dynamics of FtsZ can be determined using a method like Test A described below.

Test A. Determining the Impact of the Compounds of the Invention on FtsZ Polymerization Dynamics.

Compound-induced alteration in FtsZ polymerization dynamics can be tested using a light scattering-based competition binding assay using purified FtsZ. Upon addition of GTP, FtsZ self-associates to form polymeric structures that scatter light at 340 nm to a greater extent than the monomeric protein. The impact of the compounds of the invention on the polymerization dynamics of FtsZ can be detected by an increase of decrease in the extent of GTP-induced light scattering relative to that observed in the absence of compound. Quantitation of the overall extent of light scattering at a given compound concentration provides an indication of the potency of that compound at altering FtsZ polymerization dynamics.

The ability of a compound of the invention to inhibit FtsZ GTPase activity can be determined using a method like Test B described below.

Test B. Determining the FtsZ GTPase Inhibitory Activities of Compounds of the Invention.

Compound-induced inhibition of the FtsZ GTPase activity can be tested using a colorimetric assay in which the inorganic phosphate (Pi) released upon FtsZ-catalyzed hydrolysis of GTP reacts with malachite green and molybdate under acidic conditions to form a ternary complex that absorbs light at 650 nm, thus enabling quantitation of Pi levels by recording the absorbance at 650 nm (A650). All reactions are conducted in triplicate in 96-well microtiter plates. Differing concentrations (ranging from 0 to 1.5 mM) of compound are combined with 1 mM GTP and 20 mM CaCl₂, the latter being used because FtsZ GTPase activity requires the presence of Ca2+ ions. The reactions will be initiated by addition of 2 μM FtsZ and allowed to incubate for 60 minutes at room temperature. Following incubation, the reactions will be stopped by adding 80 μl of an acidic malachite green-molybdate solution containing 0.3 mg/ml malachite green oxalate, 2 mg/ml sodium molybdate, 0.5 mg/ml Triton X-100, and 0.7 N HCl. For the purposes of generating a standard curve, each experiment includes reactions containing known concentrations (ranging from 0 to 10 μM) of monobasic potassium phosphate (KH2PO4) in place of FtsZ. Ten minutes following addition of the acidic malachite green-molybdate solution, the A650 value for each reaction are recorded using a microtiter plate reader. A standard curve of A650 versus Pi concentration is constructed using the average A650 value obtained for each known KH2PO4 concentration. This standard curve is then fit by linear regression analysis to yield the quantitative relationship between A650 and Pi concentration. The resulting relationship as well as the average A650 value for each test reaction is used to calculate the concentrations of Pi released by the GTPase activity of FtsZ. The released Pi concentration in the absence of test compound is set as the mark for 100% GTPase activity, and is used to calculate the percent GTPase activities in reactions containing test compounds. The percent GTPase activity is then plotted as a function of log(compound concentration), with the resulting curves being fit using an appropriate sigmoidal relationship to obtain the compound concentrations at which GTPase activity is inhibited by 50% (IC50 values). These IC50 values provide quantitative measures of the potencies with which the test compounds of the invention inhibit FtsZ GTPase activity. Results from Test B for representative compounds of the invention are shown in the following Table.

Inhibition of S. aureus FtsZ GTPase Activity by Representative Compounds of the Invention Compound ¹IC₅₀ (μM) Example 19 <100 Example 22 <100 ¹IC₅₀ reflects the compound concentration at which FtsZ GTPase activity is inhibited by 50%.

The antibacterial activity of a compound of the invention can be determined using methods like Test C and Test D described below.

Test C. Planktonic (Free-Living) Antibacterial Assay.

Planktonic antibacterial activity can be determined using a broth microdilution assay in which log-phase bacteria are grown at 37° C. in appropriate medium containing two-fold serial dilutions of a compound to yield a final concentration ranging from 256 to 0.1 μg/ml. For determination of minimal inhibitory concentration (MIC) values, bacterial growth is monitored after 24 to 48 hours by measuring optical density at 600 nm. MIC values reflect the minimal compound concentrations at which bacterial growth is completely inhibited. The minimal inhibitory concentration against methicillin-Sensitive Staphylococcus aureus (MSSA) for each of the following representative compounds of the invention was determined to be less than 32 μg/ml. Data for representative compounds of the invention is provided below.

TABLE X Minimal Inhibitory Concentrations against MSSA for representative compounds of the Invention MIC vs MSSA MIC vs MRSA Example Structure (ug/ml) (ug/ml) Example 3

≦32 Example 5

≦8  Example 7

≦8  Example 9

≦8  Example 10

≦8  ≦8 Example 11

≦8  ≦8 Example 12

≦8  Example 13

≦8  ≦8 Example 15

≦8  ≦8 Example 19

≦8  ≦8 Example 22

≦8  Example 23

≦8  Test D. Biofilm Antibacterial Assay

Bacteria growing in biofilms frequently exhibit altered sensitivities to antimicrobial agents relative to free-living bacteria. It is therefore important to assess the antibacterial activities of the compounds of the invention against bacteria growing as biofilms. Toward this end, well-established protocols can be used to determine biofilm susceptibilities to compounds. The biofilms are prepared by seeding overnight cultures of bacteria on top of sterile polycarbonate membranes resting on Tryptic Soy Agar (TSA) plates. The plates are inverted and incubated for 48 hours at 37° C. After 48 hours of incubation in the absence of antibiotic, colony biofilms are transferred to fresh TSA plates containing differing compound concentrations. These plates are incubated at 37° C. and the biofilms sampled every hour for four hours and after 24 hours. The biofilms are sampled by placing the membrane and associated bacteria into a tube containing phosphate-buffered water and vortexing at high speed. The resulting cell suspensions are serially diluted and the viable bacteria counted by drop-plating on R2A agar plates. The extent of bacterial killing is calculated relative to the cell count at time zero. Antibacterial potencies are defined by the minimum drug concentrations that eradicate the biofilm (i.e., minimum biofilm eradication concentrations, MBEC).

The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES Example 1 Preparation of Compound

3-([1,1′:3′,1″-Terphenyl]-5′-yl)-1-chloro-6,7-dimethoxyisoquinoline (25 mg) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]PdII) (4 mg, 0.1 eq.) were combined in a flask and air was evacuated and replaced with N₂. Dimethylamine (2 mL) followed by LHMDS 1M in THF (0.02 mL, 1.5 eq.) was then added, and reaction was allowed to stir overnight at room temperature. Reaction mixture was then diluted with EtOAc and washed with NH₄Cl. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 40% EtOAc/hexane yielding product as a tan solid (24 mg, 94% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.28 (m, 2H), 7.72 (m, 1H), 7.69-7.67 (m, 4H), 7.63 (s, 1H), 7.44-7.40 (m, 4H), 7.37 (s, 1H), 7.34-7.30 (m, 2H), 7.18 (s, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.08 (s, 6H). ¹³C NMR (100 MHz) (CDCl₃) δ 160.49, 152.24, 148.90, 147.18, 142.05, 141.62, 141.26, 135.54, 128.79, 127.39, 127.36, 125.83, 124.55, 115.91, 106.06, 105.01, 56.03, 55.97, 42.99. MP: 102-104° C.

The requisite intermediate was prepared as follows:

a. Preparation of Compound

To a solution of 5,6-dimethoxy-1-indanone (2 g) in 40 mL MeOH was added concentrated HCl (1.04 mL). Butyl nitrite (1.34 mL, 1.1 eq.) in 10 mL MeOH was then added at 40° C. and reaction mixture was allowed to stir for 2.5 hours. Reaction mixture was then cooled to room temperature and precipitate was filtered out and dried yielding a pale yellow solid (2.14 g, 93% yield). ¹H NMR (400 MHz) (DMSO-d₆) δ 12.44 (s, 1H), 7.18 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.66 (s, 2H). ¹³C NMR (100 MHz) (DMSO-d₆) δ 187.54, 155.96, 154.66, 149.29, 142.46, 130.48, 108.56, 104.49, 55.87, 55.67, 27.79. MP: 221-223° C.

b. Preparation of Compound

2-(Hydroxyimino)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (2.14 g) was added to a 20 mL solution of 8% NaOH and heated to 50° C. p-toluenesulfonyl chloride (2.46 g, 1.33 eq.) was then added in portions. Reaction mixture was heated to 80° C. for 15 minutes the cooled to room temperature. Precipitate was filtered off and filtrate was collected and acidified with concentrated HCl to a pH of 3-4. Resulting precipitate was collected and dried yielding a tan solid (1.84 g, 86% yield). ¹H NMR (400 MHz) (DMSO-d₆) δ 13.05 (s, 1H), 7.51 (s, 1H), 7.15 (s, 1H), 4.19 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H). ¹³C NMR (100 MHz) (DMSO-d₆) δ 167.10, 151.86, 147.71, 126.36, 121.36, 119.07, 114.11, 113.94, 55.80, 5.62, 22.00. IR (thin film NaCl) 2982, 2945, 2634, 2255, 1686, 1601, 1573, 1535, 1524, 1468, 1456, 1441, 1395, 1322, 1300, 1283, 1224, 1199, 1174, 1701, 1026, 987, 928, 880, 862, 839, 787, 762, 742, 666, 600. MP: 153-156° C.

c. Preparation of Compound

2-(Cyanomethyl)-4,5-dimethoxybenzoic acid (500 mg) was added to a 3-neck flask with a stir bar under N2 and dissolved in 7 mL anhydrous DCM. Oxalyl chloride (0.79 mL, 4 eq.) was then added followed by catalytic amount of anhydrous DMF. Reaction was allowed to stir for 2 hours at room temperature then solvents were evaporated and placed on vacuum pump for 30 minutes. Crude product was then taken immediately to the next step.

d. Preparation of Compound

2-(Cyanomethyl)-4,5-dimethoxybenzoyl chloride was suspended in 30 mL anhydrous ether and HBr was bubbled through the solution for 2 hours. Reaction mixture was diluted with CHCl₃, washed with NaHCO₃, and organic layer was dried over sodium sulfate and concentrated. DCM was then added to precipitate product out. Precipitate was then filtered and dried yielding a brown solid (498 mg, 78% yield). ¹H NMR (400 MHz) (DMSO-d₆) δ 12.03 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 6.79 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H). ¹³C NMR (100 MHz) (DMSO-d₆) δ 161.52, 153.41, 148.78, 133.38, 128.86, 128.16, 107.71, 106.60, 106.33, 55.77, 55.53. MP: 249-253° C.

e. Preparation of Compound

3-Bromo-6,7-dimethoxyisoquinolin-1(2H)-one (100 mg) was combined with terphenyl boronic acid (193 mg, 2 eq.), Pd(OAc)₂ (8 mg, 0.1 eq.), XPhos (33.5 mg, 0.2 eq.), and K₂CO₃ (194 mg, 4 eq.) in a flask and degassed. 6 mL ACN and 3 mL of H₂O were then added and solution was heated at 100° C. for 1.5 hours. Reaction mixture was cooled to room temperature then diluted with EtOAc and washed with NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 70% EtOAc/hexane yielding product as a white solid (108 mg, 71% yield). ¹H NMR (400 MHz) (CDCl₃) δ11.20 (s, 1H), 7.91 (d, J=4 Hz, 2H), 7.84 (t, J=4 Hz, 1H), 7.74-7.72 (m, 4H), 7.65 (s, 1H), 7.41-7.38 (m, 4H), 7.34-7.30 (m, 2H), 6.93 (s, 1H), 6.80 (s, 1H), 3.95 (s, 3H), 3.71 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 163.60, 153.96, 149.32, 142.67, 140.46, 138.53, 135.62, 133.92, 128.97, 127.88, 127.30, 126.77, 124.01, 119.03, 107.41, 106.58, 104.45, 56.11, 53.38. MP: 256-260° C.

f. Preparation of Compound

3-([1,1′:3′,1″-Terphenyl]-5′-yl)-6,7-dimethoxyisoquinolin-1(2H)-one (105 mg) was refluxed at 110° C. in 3 mL POCl₃ for 3 hours. POCl₃ was then removed under vacuum. Chromatography achieved using ISCO max gradient 70% EtOAc/hexane yielding product as a beige solid (84 mg, 77% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.29 (d, J=4.0 Hz, 2H), 8.01 (s, 1H), 7.86 (t, J=4 Hz, 1H), 7.79-7.76 (m, 4H), 7.57 (s, 1H), 7.54-7.50 (m, 4H), 7.45-7.41 (m, 2H), 7.18 (s, 1H), 4.11 (s, 3H), 4.08 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 153.77, 151.15, 149.17, 142.36, 141.16, 139.44, 135.32, 128.80, 127.53, 127.42, 126.45, 124.60, 121.84, 115.63, 105.47, 104.61, 56.23. MP: 183-184° C.

Example 2 Preparation of Compound

3-([1,1′:3′,1″-Terphenyl]-5′-yl)-1-chloro-6,7-dimethoxyisoquinoline (25 mg) was refluxed at 185° C. for 2.5 hours in 3 mL phenol. Reaction mixture was then cooled to room temperature and diluted with H₂O, washed with 1N NaOH, and extracted with EtOAc. Organic layer was concentrated and remaining phenol was removed under reduced pressure. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding white solid (16 mg, 57% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.08 (m, 2H), 7.73 (s, 1H), 7.68 (t, J=4.0 Hz, 1H), 7.63 (s, 1H), 7.57-7.55 (m, 4H), 7.43-7.36 (m, 6H), 7.34-7.28 (m, 4H), 7.28-7.20 (m, 1H), 7.10 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 158.84, 154.27, 153.39, 150.13, 146.18, 141.80, 141.19, 139.93, 136.00, 129.20, 128.72, 127.38, 127.20, 125.54, 124.48, 124.18, 122.33, 113.81, 110.85, 105.59, 102.78, 56.20, 56.06. MP: 188-192° C.

Example 3 Preparation of Compound

Guanidine HCl (13 mg, 3 eq.) was added to a suspension of NaH 60% dispersion in mineral oil (6 mg, 3 eq.) in 2 mL anhydrous DMSO. Reaction was heated at 60° C. for 30 minutes then 3-([1,1′-biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (20 mg) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]PdII) (5 mg, 0.1 eq.) were then quickly added, and the reaction was heated at 100° C. overnight. Reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 5% MeOH/DCM yielding product as a brown solid (10.5 mg, 50%). ¹H NMR (400 MHz) (DMSO-d₆) δ 8.28 (s, 1H), 8.28 (m, 2H), 8.11 (s, 1H), 7.97 (s, 1H), 7.90 (d, J=12 Hz, 4H), 7.56 (t, J=12 Hz, 4H), 7.51-7.44 (m, 3H), 4.04 (s, 3H), 3.99 (s, 3H).

Example 4 Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (20 mg) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]PdII) (4 mg, 0.1 eq.) were combined in a flask and air was evacuated and replaced with N₂. Dimethylamine (2 mL) followed by LHMDS 1M in THF (0.02 mL, 1.5 eq.) was then added, and reaction was allowed to stir overnight at room temperature. Reaction mixture was then diluted with EtOAc and washed with NH₄Cl. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 40% EtOAc/hexane yielding product as a tan oil (20 mg, quantitative). ¹H NMR (400 MHz) (CDCl₃) δ 8.30 (t, J=4 Hz, 1H), 8.05 (dt, J=8 Hz, J=4 Hz, 1H), 7.64-7.62 (m, 2H), 7.58 (s, 1H), 7.52-7.49 (m, 1H), 7.47-7.44 (m, 1H), 7.42-7.38 (m, 2H), 7.36 (s, 1H), 7.32-7.28 (m, 1H), 7.03 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.06 (s, 6H). ¹³C NMR (100 MHz) (CDCl₃) δ 152.23, 148.86, 147.21, 145.89, 141.65, 141.47, 140.68, 135.55, 128.94, 128.73, 127.27, 127.20, 126.75, 125.50, 125.43, 119.97, 115.85, 110.35, 106.06, 105.02, 56.02, 55.95, 42.95.

The requisite intermediate was prepared as follows:

a. Preparation of Compound

3-Bromo-6,7-dimethoxyisoquinolin-1(2H)-one (550 mg) was combined with 3-biphenyl boronic acid (768 mg, 2 eq.), Pd(OAc)₂ (43.5 mg, 0.1 eq.), XPhos (185 mg, 0.2 eq.), and K₂CO₃ (1.07 g, 4 eq.) in a flask and degassed. 15 mL ACN and 7.5 mL of H₂O were then added and solution was heated at 100° C. for 1.5 hours. Reaction mixture was cooled to room temperature then diluted with EtOAc and washed with NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 70% EtOAc/hexane yielding product as a white solid (540 mg, 78% yield). ¹H NMR (400 MHz) (CDCl₃) δ 9.98 (s, 1H), 7.97 (m, 1H), 7.78 (s, 1H), 7.75-7.67 (m, 4H), 7.60 (t, J=16 Hz, 1H), 7.50-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.01 (s, 1H), 6.81 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 163.48, 153.93, 149.28, 142.03, 140.35, 138.47, 135.10, 133.92, 129.54, 128.93, 127.81, 127.75, 127.17, 125.07, 124.97, 118.99, 107.38, 106.57, 104.19, 56.11, 56.09. MP: 229-231° C.

b. Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-6,7-dimethoxyisoquinolin-1(2H)-one (130 mg) was refluxed at 110° C. in 3 mL POCl₃ for 3 hours. POCl₃ was then removed under vacuum. Chromatography achieved using ISCO max gradient 70% EtOAc/hexane yielding product as a beige solid (117 mg, 85% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.32 (t, J=4 Hz, 1H), 8.10-8.07 (m, 1H), 7.96 (s, 1H), 7.73-7.71 (m, 2H), 7.66-7.64 (m, 1H), 7.57 (t, J=10 Hz, 2H), 7.52-7.48 (m, 1H), 7.18 (s, 1H), 4.11 (s, 3H), 4.08 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 153.72, 151.09, 149.21, 149.11, 141.79, 141.17, 138.88, 135.32, 129.19, 128.76, 127.45, 127.40, 127.32, 125.64, 125.55, 121.75, 115.44, 105.43, 104.56, 56.22.

c. Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (20 mg) in 1 mL MeI was heated in a sealed tube at 100° C. overnight. Solution was concentrated and salt was re-crystallized in EtOAc/hexane yielding product as an off-white solid (20 mg, 71% yield). ¹H NMR (400 MHz) (DMSO-d₆) δ 8.26 (s, 1H), 8.00 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.79-7.75 (m, 4H), 7.73 (s, 1H), 7.70 (s, 1H), 7.53-7.51 (m, 2H), 7.48-7.44 (m, 1H), 4.42 (s, 3H), 4.12 (s, 1H), 4.07 (s, 1H).

Example 5 Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxy-2-methylisoquinolin-2-ium iodide (28 mg) in 3 mL dimethylamine was stirred at room temperature overnight. Solution was concentrated and salt was re-crystallized in EtOAc/hexane yielding product as a tan solid (20 mg, 71% yield). ¹H NMR (400 MHz) (CDCl₃) δ 7.87 (t, J=4 Hz, 1H), 7.79-7.77 (m, 1H), 7.75 (s, 1H), 7.73-7.69 (m, 3H), 7.67-7.63 (m, 1H), 7.56 (s, 1H), 7.52-7.48 (m, 2H), 7.44-7.42 (m, 1H), 7.39 (s, 1H), 4.15 (s, 3H), 4.12 (s, 3H), 3.63 (s, 6H). ¹³C NMR (100 MHz) (CDCl₃) δ 158.72, 156.93, 151.86, 144.86, 142.53, 139.56, 136.89, 134.22, 129.97, 129.06, 128.99, 128.15, 127.63, 127.31, 120.07, 119.40, 106.87, 106.64, 57.11, 45.58, 45.19, 34.54.

Example 6 Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (20 mg) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]PdII) (4 mg, 0.1 eq.) were combined in a flask and air was evacuated and replaced with N₂. Methylamine (2 mL) followed by LHMDS 1M in THF (0.02 mL, 1.5 eq.) was then added, and reaction was allowed to stir overnight at room temperature. Reaction mixture was then diluted with EtOAc and washed with NH₄Cl. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a clear oil (20 mg, quantitative). ¹H NMR (400 MHz) (CDCl₃) δ 8.31 (t, J=4 Hz, 1H), 8.06 (dt, J=8 Hz, J=4 Hz, 1H), 7.64-7.62 (m, 2H), 7.51-7.49 (m, 1H), 7.46 7.43 (m, 1H), 7.41-7.37 (m, 2H), 7.34 (s, 1H), 7.31-7.27 (m, 1H), 6.99 (s, 1H), 6.91 (s, 1H), 4.92 (bs, 1H), 3.93 (s, 6H), 3.21 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.47, 152.18, 149.09, 141.73, 141.37, 140.97, 134.06, 128.85, 128.72, 127.16, 126.67, 125.53, 125.46, 112.13, 106.62, 106.56, 101.17, 56.07, 55.92, 28.97.

Example 7 Preparation of Compound

Guanidine HCl (38 mg, 3 eq.) was added to a suspension of NaH 60% dispersion in mineral oil (10 mg, 3 eq.) in 5 mL anhydrous DMSO. Reaction was heated at 60° C. for 30 minutes then 3-([1,1′-biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (50 mg) and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]PdII) (9 mg, 0.1 eq.) were then quickly added, and the reaction was heated at 100° C. overnight. Reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 5% MeOH/DCM yielding product as a tan solid (20 mg, 38%). ¹H NMR (400 MHz) (DMSO-d₆) δ 11.36 (bs, 1H), 8.26-8.19 (m, 3H), 7.96 (d, J=8 Hz, 1H), 7.81-7.74 (m, 3H), 7.64 (t, J=16 Hz, 1H), 7.55-7.50 (m, 3H), 7.43 (t, J=12 Hz, 1H), 4.05 (s, 3H), 3.98 (s, 3H). ¹³C NMR (100 MHz) (DMSO-d₆) δ 156.33, 153.35, 150.62, 145.03, 140.98, 140.00, 139.01, 135.06, 129.70, 128.97, 127.68, 126.86, 125.15, 124.51, 113.43, 113.15, 106.57, 102.93, 56.92, 55.82, 54.85. MP: 255-257° C.

Example 8 Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (50 mg) and CuCN (24 mg, 2 eq.) in 2 mL DMSO was heated at 140° C. for 3 hours. Reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a beige solid (13 mg, 27% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.25 (t, J=4 Hz, 1H), 8.10 (s, 1H), 8.00-7.98 (m, 1H), 7.64-7.62 (m, 2H), 7.60-7.57 (m, 1H), 7.50 (t, J=16 Hz, 1H), 7.43-7.39 (m, 3H), 7.34-7.30 (m, 1H), 7.11 (s, 1H), 4.03 (s, 3H), 4.00 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.28, 152.56, 150.73, 142.00, 140.98, 138.53, 134.11, 131.60, 129.34, 128.82, 127.86, 127.53, 127.28, 125.68, 125.63, 125.52, 118.91, 116.57, 105.18, 102.74, 56.46, 56.34.

Example 9 Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-1-chloro-6,7-dimethoxyisoquinoline (50 mg) in 0.5 mL ethylenediamine was heated at 150° C. in a sealed tube overnight. Solution was then cooled to room temperature and concentrated. Chromatography achieved using silica column max gradient 10% MeOH/DCM/1% NH₄OH yielding product as a beige oil (12 mg, 23% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.26 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.42-7.38 (m, 2H), 7.34 (s, 1H), 7.30 (t, J=16 Hz, 1H), 6.99 (d, J=4 Hz, 2H), 5.50 (bs, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.75 (q, J=16 Hz, 2H), 3.08 (t, J=12 Hz, 2H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.01, 152.23, 149.13, 147.72, 141.68, 141.37, 140.93, 134.17, 128.88, 128.74, 127.27, 127.19, 126.66, 125.48, 125.39, 112.09, 106.70, 106.54, 101.33, 56.18, 55.93, 44.31, 41.44. IR (thin film NaCl) 3356, 2932, 1623, 1573, 1535, 1502, 1464, 1425, 1250, 1219, 1166, 1131, 1023, 859, 800, 760, 734, 701, 404.

Example 10 Preparation of Compound

To a cooled solution of di-Boc protected guanidine compound (78 mg) in 1.5 mL DCM was added 1.5 mL trifluoroacetic acid. Reaction was removed from an ice bath and then allow to stir at room temperature for 2 hours. Solvents were evaporated. The solid residue was then taken back up in DCM and precipitate was filtered off yielding product as a grayish white solid (22 mg, 42% yield over 2 steps). ¹H NMR (400 MHz) (MeOD₄) δ 8.25 (m, 1H), 8.08 (s, 1H), 8.04 (d, J=4 Hz, 1H), 7.58-7.56 (m, 3H), 7.47 (t, J=16 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.33 (s, 1H), 7.29 (s, 1H), 4.95 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 1.28 (s, 9H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound

6,7-Dimethoxy-1-methylisoquinolin-3-ol (540 mg) and Et₃N (0.9 mL, 2 eq.) in DCM were cooled to −78° C. Tf₂O (0.64 mL, 1.2 eq.) was slowly added to the mixture and was stirred for 30 minutes at −78° C. Reaction was then quickly diluted with additional DCM and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a white solid (737 mg, 85% yield). ¹H NMR (400 MHz) (CDCl₃) δ 7.29 (s, 1H), 7.29 (s, 1H), 7.12 (s, 1H), 4.07 (s, 3H), 4.07 (s, 3H), 2.90 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 156.54, 153.80, 150.67, 135.47, 123.35, 107.62, 105.39, 103.73, 56.23, 56.11, 22.03.

b. Preparation of Compound

6,7-Dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (200 mg), 3-hydroxyphenylboronic acid (157 mg, 2 eq.), Pd(OAc)₂ (13 mg, 0.1 eq.), XPhos (54 mg, 0.2 eq.), and Cs₂CO₃ (650 mg, 3.5 eq.) were combined in a flask with 9 mL ACN and 3 mL H₂O and degassed. Reaction mixture was then refluxed at 100° C. for 5 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as white solid (78 mg, 46% yield). ¹H NMR (400 MHz) (CDCl₃) δ 7.66-7.63 (m, 2H), 7.38 (d, J=4 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 7.17 (s, 1H), 7.00 (s, 1H), 6.73-6.71 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.87 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 156.74, 156.12, 152.88, 149.93, 149.19, 141.46, 133.56, 129.85, 122.35, 118.72, 115.49, 115.25, 114.59, 105.66, 103.87, 56.05, 56.01, 22.20. IR (thin film NaCl) 3002, 2255, 1621, 1576, 1501, 1468, 1425, 1409, 1372, 1324, 1292, 1245, 1222, 1205, 1178, 1159, 1062, 1027, 995, 973, 924, 913, 896, 878, 846, 837, 781, 762, 745, 738, 726, 691, 645.

c. Preparation of Compound

3-(6,7-Dimethoxy-1-methylisoquinolin-3-yl)phenol (175 mg) and Et₃N (0.16 mL, 2 eq.) in DCM were cooled to −78° C. Tf₂O (0.12 mL, 1.2 eq.) was slowly added to the mixture and was stirred for 30 minutes at −78° C. Reaction was then quickly diluted with additional DCM and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a white solid (230 mg, 91% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.14 (d, J=8 Hz, 1H), 8.09 (s, 1H), 7.82 (s, 1H), 7.56 (t, J=16 Hz, 1H), 7.31 (s, 1H), 7.29 (dd, J=8 Hz, J=4 Hz, 1H), 7.15 (s, 1H), 4.08 (s, 3H), 4.07 (s, 3H), 2.98 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 156.31, 152.87, 150.31, 150.23, 146.60, 142.99, 133.24, 130.31, 126.31, 122.79, 120.29, 119.56, 117.23, 114.79, 105.81, 103.93, 56.07, 56.03, 22.68.

d. Preparation of Compound

3-(6,7-Dimethoxy-1-methylisoquinolin-3-yl)phenyl trifluoromethanesulfonate (130 mg), 4-t-butylphenylboronic acid (108 mg, 2 eq.), Pd(OAc)₂ (7 mg, 0.1 eq.), XPhos (29 mg, 0.2 eq.), and K₂CO₃ (147 mg, 3.5 eq.) in 3 mL ACN and 1.5 mL H₂O were combined in a flask and degassed. Reaction mixture was heated to 95° C. for 2 hours. Solution was then cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 40% EtOAc/hexane yielding product as a white solid (121 mg, 97% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.35-8.34 (m, 1H), 8.08 (d, J=8 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J=8 Hz, 2H), 7.63 (d, J=8 Hz, 1H), 7.56 (t, J=16 Hz, 1H), 7.53 (d, J=8 Hz, 2H), 7.33 (s, 1H), 7.16 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.00 (s, 3H), 1.41 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 155.95, 152.67, 150.26, 149.84, 149.25, 141.47, 140.63, 138.58, 133.47, 129.01, 126.95, 126.71, 125.69, 125.65, 125.53, 122.32, 114.47, 105.72, 103.97, 56.02, 34.55, 31.40, 22.74.

e. Preparation of Compound

3-(4′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxy-1-methylisoquinoline (100 mg) and SeO₂ (32 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (80 mg, 77% yield). ¹H NMR (400 MHz) (CDCl₃) δ 10.40 (s, 1H), 8.68 (s, 1H), 8.34 (m, 1H), 8.14 (s, 1H), 8.07 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 3H), 7.52 (t, J=16 Hz, 1H), 7.45 (d, J=8 Hz, 2H), 7.13 (s, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 1.32 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 196.81, 153.33, 152.83, 149.76, 141.84, 139.20, 138.29, 135.44, 129.26, 127.43, 126.95, 125.76, 125.59, 125.35, 122.19, 120.01, 104.99, 103.59, 56.29, 56.02, 34.57, 31.38.

f. Preparation of Compound

3-(4′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxyisoquinoline-1-carboxaldehyde (76 mg) in 5 mL ethanol was treated slowly with NaBH₄ (20 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a pearly, gold solid (59 mg, 78% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.25-8.24 (m, 1H), 7.99-7.97 (m, 1H), 7.85 (s, 1H), 7.57-7.54 (m, 3H), 7.47 (t, J=12 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.08 (s, 1H), 6.96 (s, 1H), 5.22 (t, J=12 Hz, 1H), 5.10 (d, J=4 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.63, 153.20, 150.49, 150.43, 147.65, 141.66, 139.60, 138.31, 133.81, 129.11, 127.11, 126.93, 125.76, 125.40, 125.27, 119.80, 115.29, 105.86, 101.30, 61.41, 56.12, 56.06, 34.57, 31.39.

g. Preparation of Compound

To a solution of (3-(4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxyisoquinolin-1-yl)methanol (39 mg), PPh₃ (35 mg, 1.5 eq.), and 1,3-bis(tert-butoxycarbonyl)guanidine (47 mg, 2 eq.) in 3 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.03 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H₂O were added, and the solution was concentrated. Solid was then re-dissolved in DCM and passed through silica column and resulting crude product was taken to next step.

Example 11 Preparation of Compound

To a cooled solution of di-Boc protected guanidine compound (78 mg) in 1.5 mL DCM was added 1.5 mL trifluoroacetic acid. The reaction mixture was removed from the ice bath and then allowed to stir at room temperature for 2 hours. The solvent was evaporated. The solid residue was then taken back up in DCM and precipitate was filtered off yielding product as a grayish white solid (22 mg, 42% yield over 2 steps). ¹H NMR (400 MHz) (MeOD₄) δ 8.21 (m, 1H), 8.11-8.07 (m, 2H), 7.61 (m, 1H), 7.55-7.47 (m, 2H), 7.43-7.41 (m, 1H), 7.36-7.30 (m, 3H), 7.27 (s, 1H), 4.92 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 1.31 (s, 9H).

The requisite intermediate was prepared as follows:

a. Preparation of Compound

3-(6,7-Dimethoxy-1-methylisoquinolin-3-yl)phenyl trifluoromethanesulfonate (100 mg), 3-t-butylphenylboronic acid (50 mg, 1.2 eq.), Pd(OAc)₂ (5 mg, 0.1 eq.), XPhos (22 mg, 0.2 eq.), and K₂CO₃ (390 mg, 3.5 eq.) in 4 mL ACN and 2 mL H₂O were combined in a flask and degassed. Reaction mixture was heated to 95° C. for 2 hours. Solution was then cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a pearly oil (97 mg, quantitative). ¹H NMR (400 MHz) (CDCl₃) δ 8.33 (m, 1H), 8.12-8.10 (m, 1H), 7.89 (s, 1H), 7.74 (s, 1H), 7.65-7.53 (m, 1H), 7.59 (d, J=8 Hz, 1H), 7.56-7.54 (m, 1H), 7.45-7.44 (m, 2H), 7.33 (s, 1H), 7.16 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.01 (s, 3H), 1.44 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 155.98, 152.69, 151.55, 149.86, 149.26, 142.35, 141.33, 140.68, 133.48, 129.04, 129.01, 128.23, 127.06, 125.91, 125.72, 124.64, 124.50, 124.29, 122.34, 114.54, 105.74, 103.97, 56.04, 54.01, 34.89, 31.48, 22.75.

b. Preparation of Compound

3-(3′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxy-1-methylisoquinoline (92 mg) and SeO₂ (25 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (55 mg, 58% yield). ¹H NMR (400 MHz) (CDCl₃) δ 10.39 (s, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 8.07 (d, J=4 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.53 (t, J=12 Hz, 1H), 7.46-7.44 (m, 1H), 7.36-7.35 (m, 2H), 7.11 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 1.34 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 196.86, 153.26, 152.79, 151.71, 149.69, 147.04, 142.67, 141.02, 139.21, 135.42, 129.29, 128.54, 127.80, 125.81, 125.52, 124.61, 124.54, 124.47, 122.19, 120.07, 104.99, 103.52, 56.31, 56.07, 34.89, 31.47.

c. Preparation of Compound

3-(3′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxyisoquinoline-1-carbaldehyde (52 mg) in 4 mL ethanol was treated slowly with NaBH₄ (14 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a yellow oil (27 mg, 52% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.24 (t, J=4 Hz, 1H), 8.03-8.01 (m, 1H), 7.88 (s, 1H), 7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.51 (t, J=12 Hz, 1H), 7.45-7.42 (m, 1H), 7.36-7.35 (m, 2H), 7.12 (s, 1H), 6.98 (s, 1H), 5.39 (bs, 1H), 5.12 (s, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.33 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.60, 153.16, 151.69, 150.40, 147.62, 142.51, 141.06, 139.64, 133.80, 129.14, 128.55, 127.49, 125.67, 125.47, 124.61, 124.52, 124.46, 119.79, 115.38, 105.87, 101.22, 61.39, 56.13, 34.88, 31.47.

d. Preparation of Compound

(3-(3′-(tert-Butyl)-[1,1′-biphenyl]-3-yl)-6,7-dimethoxyisoquinolin-1-yl)methanol (27 mg), PPh₃ (25 mg, 1.5 eq.), and 1,3-bis(tert-butoxycarbonyl)guanidine (33 mg, 2 eq.) in 3 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.02 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H₂O were added, and the solution was concentrated. Solid was then re-dissolved in DCM and passed through silica column and resulting crude product was taken to next step.

Example 12 Preparation of Compound

To a cooled solution of di-Boc protected guanidine compound (75 mg) in 1.5 mL DCM was added 1.5 mL trifluoroacetic acid. Reaction was taken off ice bath and stirred at room temperature for 2 hours then solvents were evaporated. Solid was then taken back up in DCM and precipitate was filtered off yielding product as a grayish white solid (40 mg, 93% yield over 2 steps). ¹H NMR (400 MHz) (MeOD₄) δ 8.40 (m, 1H), 8.22 (s, 1H), 8.20 (m, 1H), 7.76-7.74 (m, 2H), 7.68 (dt, J=8 Hz, J=4 Hz, 1H), 7.61 (t, J=16 Hz, 1H), 7.53-7.49 (m, 2H), 7.46 (s, 1H), 7.42-7.38 (m, 2H), 5.07 (s, 2H), 4.07 (s, 3H), 4.05 (s, 3H). ¹³C NMR (100 MHz) (MeOD₄) δ 159.56, 155.01, 152.42, 151.82, 149.44, 143.09, 142.54, 141.25, 135.93, 130.32, 129.96, 128.54, 128.19, 128.10, 126.77, 122.05, 117.22, 107.35, 103.15, 56.64, 56.60, 45.08. The requisite intermediate was prepared as follows:

a. Preparation of Compound

6,7-Dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (575 mg), 3-biphenylboronic acid (390 mg, 1.2 eq.), Pd(OAc)₂ (37 mg, 0.1 eq.), XPhos (156 mg, 0.2 eq.), and K₂CO₃ (792 mg, 3.5 eq.) were combined in a flask with 9 mL ACN and 3 mL H₂O and degassed. Reaction mixture was then refluxed at 100° C. for 5 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as white solid (473 mg, 81% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.36 (m, 1H), 8.11-8.09 (m, 1H), 7.89 (s, 1H), 7.75-7.73 (m, 2H), 7.64-7.62 (m, 1H), 7.58 (t, J=12 Hz, 2H), 7.50 (t, J=16 Hz, 1H), 7.40 (t, J=12 Hz, 1H), 7.33 (s, 1H), 7.16 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.01 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 155.99, 152.69, 149.87, 149.15, 141.64, 141.49, 140.71, 133.47, 129.08, 128.70, 127.33, 127.25, 126.83, 125.77, 122.35, 114.51, 105.72, 103.96, 56.02, 22.76.

b. Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-6,7-dimethoxy-1-methylisoquinoline (200 mg) and SeO₂ (75 mg, 1.2 eq.) in 10.5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (175 mg, 84% yield). ¹H NMR (400 MHz) (CDCl₃) δ 10.50 (s, 1H), 8.77 (s, 1H), 8.44 (s, 1H), 8.23-8.18 (m, 2H), 7.75-7.66 (m, 3H), 7.63 (t, J=16 Hz, 1H), 7.52 (t, J=16 Hz, 2H), 7.44-7.42 (m, 1H), 7.22 (s, 1H), 4.14 (s, 3H), 4.09 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 196.80, 153.30, 152.83, 149.61, 147.06, 141.98, 141.19, 139.26, 135.43, 129.34, 129.34, 128.83, 127.58, 127.49, 127.31, 125.66, 125.62, 122.19, 120.04, 104.99, 103.55, 56.30, 56.05.

c. Preparation of Compound

3-([1,1′-Biphenyl]-3-yl)-6,7-dimethoxyisoquinoline-1-carboxaldehyde (160 mg) in 7 mL ethanol was treated slowly with NaBH₄ (50 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a yellow solid (98 mg, 61% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.36-8.35 (m, 1H), 8.13-8.11 (m, 1H), 7.98 (s, 1H), 7.73 (d, J=8 Hz, 2H), 7.68-7.66 (m, 1H), 7.60 (t, J=16 Hz, 1H), 7.51 (t, J=16 Hz, 2H), 7.42 (t, J=12 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 5.35 (bs, 1H), 5.32 (s, 2H), 4.08 (s, 3H), 4.07 (s, 3H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.65, 141.81, 141.21, 129.19, 128.82, 127.44, 127.29, 127.25, 125.55, 125.51, 119.82, 115.35, 105.87, 101.29, 61.41, 56.14, 56.09.

d. Preparation of Compound

(3-([1,1′-Biphenyl]-3-yl)-6,7-dimethoxyisoquinolin-1-yl)methanol (30 mg), PPh₃ (32 mg, 1.5 eq.), and 1,3-bis(tert-butoxycarbonyl)guanidine (42 mg, 2 eq.) in 3 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.024 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H₂O were added, and the solution was concentrated. Solid was then re-dissolved in DCM and passed through silica column and resulting crude product was taken to next step.

Example 13 Preparation of Compound

To a cooled solution of di-Boc protected guanidine compound (80 mg) in 1.5 mL DCM was added 1.5 mL trifluoroacetic acid. Reaction mixture was removed from the ice bath and allowed to stirred at room temperature for 2 hours. Solvents was evaporated. The solid residue was then taken back up in DCM and precipitate was filtered off yielding product as a grayish white solid (52 mg, 95% yield over 2 steps). ¹H NMR (400 MHz) (CDCl₃) δ 9.69 (bm, 1H), 7.96 (s, 1H), 7.93 (s, 1H), 7.76-7.75 (m, 1H), 7.47-7.42 (m, 3H), 7.18 (s, 1H), 4.87 (d, J=4 Hz, 2H), 4.10 (s, 3H), 4.07 (s, 3H), 1.39 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 159.07, 154.10, 151.87, 151.77, 151.39, 148.17, 137.74, 135.25, 128.77, 126.02, 123.91, 123.54, 121.52, 117.13, 105.62, 102.59, 56.34, 56.20, 44.66, 34.83, 31.31. The requisite intermediate was prepared as follows:

a. Preparation of Compound

6,7-Dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (300 mg), 3-t-butylphenylboronic acid (183 mg, 1.2 eq.), Pd(OAc)_(z) (19 mg, 0.1 eq.), XPhos (81 mg, 0.2 eq.), and K₂CO₃ (354 mg, 3 eq.) were combined in a flask with 9 mL dioxane and 3 mL H₂O and degassed. Reaction mixture was then refluxed at 100° C. for 2 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO₃. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 40% EtOAc/hexane yielding product as a clear oil (245 mg, 83% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.14 (s, 1H), 7.92-7.89 (m, 1H), 7.81 (s, 1H), 7.45-7.44 (m, 2H), 7.31 (s, 1H), 7.15 (s, H), 4.08 (s, 3H), 4.07 (s, 3H), 3.00 (s, 3H), 1.44 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 155.86, 152.59, 151.39, 149.88, 149.70, 139.95, 133.48, 128.37, 125.13, 124.16, 123.88, 122.16, 114.45, 105.67, 103.92, 56.03, 55.99, 34.88, 31.48, 22.79.

b. Preparation of Compound

3-(3-(tert-Butyl)phenyl)-6,7-dimethoxy-1-methylisoquinoline (153 mg) and SeO₂ (61 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (97 mg, 62% yield). ¹H NMR (400 MHz) (CDCl₃) δ 10.40 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (dt, J=4 Hz, J=4 Hz, 1H), 7.42-7.40 (m, 2H), 7.13 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 1.36 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 196.96, 153.20, 152.67, 151.82, 150.35, 146.98, 138.51, 135.43, 128.67, 125.91, 124.05, 123.78, 122.07, 120.08, 104.95, 103.49, 56.30, 56.07, 34.95, 31.46.

c. Preparation of Compound

3-(3-(tert-Butyl)phenyl)-6,7-dimethoxyisoquinoline-1-carboxaldehyde (97 mg) in 5 mL ethanol was treated slowly with NaBH₄ (26 mg, 3 eq.) at room temperature. Reaction was stirred for 1 hour then 2 mL acetone was added and solution was filtered through filter paper. Filtrate was concentrated then re-dissolved in DCM and washed with H₂O. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 50% EtOAc/hexane yielding product as a pale yellow solid (50 mg, 63% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.07 (m, 1H), 7.86-7.83 (m, 1H), 7.82 (s, 1H), 7.39-7.37 (m, 2H), 7.13 (s, 1H), 6.98 (s, 1H), 5.12 (s, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.35 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 154.47, 153.14, 151.62, 150.31, 148.21, 138.90, 133.85, 128.51, 125.55, 123.97, 123.65, 119.64, 115.25, 105.84, 101.22, 61.32, 56.13, 56.10, 34.90, 31.45. IR (thin film NaCl) 3345, 2957, 1621, 1577, 1506, 1467, 1416, 1362, 1276, 1247, 1163, 1090, 1023, 991, 874, 834, 800, 701.

d. Preparation of Compound

(3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-1-yl)methanol (50 mg), PPh₃ (56 mg, 1.5 eq.), and 1,3-bis(tert-butoxycarbonyl)guanidine (74 mg, 2 eq.) in 4 mL toluene at 0° C. was added diisopropylazodicarboxylate (0.04 mL, 1.5 eq.) drop wise over 15 minutes. Reaction was stirred for 3 hours at room temperature then 2 drops H₂O were added, and the solution was concentrated. Solid was then re-dissolved in DCM and passed through silica column and resulting crude product was taken to next step.

Example 14 Preparation of Compound

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 2,3-dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-3-yl)phenyl trifluoromethanesulfonate (200 mg, 0.39 mmol), (4′-fluoro-[1,1′-biphenyl]-3-yl)boronic acid (99.3 mg, 0.58 mmol), water/acetonitrile (2 mL/6 ml), K₂CO₃ (106 mg, 0.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (20 mg, 0.039 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (5.0 mg, 0.02 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 90° C. and stirred for 12 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄. The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 10% EtOAc/hexanes afforded the title compound (180 mg, 86%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (t, 1H, J=1.68 Hz), 7.82 (d, 1H, J=2.04 Hz), 7.76 (s, 1H), 7.62-7.68 (m, 4H), 7.51-7.59 (m, 2H), 7.14-7.18 (m, 2H), 6.95 (s, 1H), 4.09 (s, 3H), 4.05 (s, 3H), 4.02 (s, 3H), 3.99 (s, 3H), 3.70 (s, 3H), 3.16 (s, 3H). The requisite intermediate was prepared as follows:

a. Preparation of Compound

A 50-mL round bottom flask equipped with a magnetic stirrer under nitrogen was charged with 6,7,8-trimethoxy-1-methylisoquinolin-3-ol (200 mg, 0.80 mmol), CH₂Cl₂ (15 mL), and triethylamine (0.22 ml, 1.60 mmol). After cooling to −70° C., triflic anhydride (0.15 ml, 0.88 mmol) was added via a syringe. The resulting reaction mixture was stirred at −70 to −4° C. for 30 min, then diluted with CH₂Cl₂ (50 mL) and washed with saturated NaHCO₃ (20 mL), brine (20 mL), dried over MgSO₄, and concentrated to afford a brown solid. The brown solid was purified on silica gel, and elution with CH₂Cl₂ afforded the title compound (210 mg, 69%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.13 (s, 1H), 6.83 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 2.96 (s, 3H).

b. Preparation of Compound

A 100-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 6,7,8-trimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (1.7 g, 4.46 mmol), (3-(benzyloxy)-4,5-dimethoxyphenyl)boronic acid (1.54 g, 5.35 mmol), water/acetonitrile (10 mL/20 ml), K₂CO₃ (1.54 mg, 11.2 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (212 mg, 0.45 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (50 mg, 0.22 mmol) was added and the solution was carefully degassed. The reaction mixture was heated to 90° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (200 mL) and washed with saturated NaHCO₃ (50 mL), brine (50 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (2.03 g, 96%) as a light yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.66 (s, 1H), 7.73-7.55 (m, 2H), 7.39-7.44 (m, 4H), 7.33-7.37 (m, 1H), 6.95 (s, 1H), 5.28 (s, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H), 3.99 (s, 314 3.94 (s, 3H), 3.15 (s, 3H).

c. Preparation of Compound

A 1-L round bottom flask equipped with a magnetic stirrer was charged with 3-(3-(benzyloxy)-4,5-dimethoxyphenyl)-6,7,8-trimethoxy-1-methylisoquinoline (2.3 g, 4.84 mmol), MeOH (250 mL), and Pd/C (10%, 200 mg). The reaction flask was sealed with septum and purge with N₂ three times; H₂ three times. The reaction mixture was stirred at room temperature under H₂ balloon for 3 hours. TLC showed the starting material was consumed. The reaction mixture was passed through a pad of Celite and washed with MeOH. The filtrate was concentrated to afford the crude title compound (1.67 g, 90%) as a grey foam. The crude product was used in next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 7.69 (s, 1H), 7.39 (d, 1H, J=1.92 Hz), 7.31 (d, 1H, J=1.96 Hz), 6.94 (s, 1H), 5.83 (s, 1H), 4.05 (s, 3H), 4.04 (s, 3H), 4.03 (s, 3H), 3.99 (s, 3H), 3.97 (s, 3H), 3.15 (s, 3H).

d. Preparation of Compound

A 500-mL round bottom flask equipped with a magnetic stirrer under nitrogen was charged with 2,3-dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-3-yl)phenol (1.66 g, 4.31 mmol), CH₂Cl₂ (100 mL), and triethylamine (1.20 ml, 8.62 mmol). After cooling to −70° C., triflic anhydride (0.80 ml, 4.74 mmol) was added via a syringe. The resulting reaction mixture was stirred at −70- to −30° C. for 30 min. The reaction mixture was diluted with CH₂Cl₂ (100 mL) and washed with saturated NaHCO₃ (50 ml), brine (50 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (2.21 g, 99%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.72 (d, 1H, J=1.88 Hz), 7.59 (s, 1H), 7.45 (d, 1H, J=1.84 Hz), 6.89 (s, 1H), 3.96 (s, 6H), 3.95 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.06 (s, 3H).

Example 15 Preparation of Compound

A solution of 3-(4″-fluoro-5,6-dimethoxy-[1,1′:3′,1″-terphenyl]-3-yl)-6,7,8-trimethoxy-1-methylisoquinoline (180 mg, 0.33 mmol) in iodomethane (3.0 mL) was stirred in a sealed vial at 100° C. for 12 hours. After cooled to room temperature, Et₂O (10 mL) was added and the solid was collected by filtration, then washed with Et₂O to afford the title compound (155 mg, 68%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (s, 1H), 7.85 (d, 1H, J=2.04 Hz), 7.78 (m, 1H), 7.50-7.64 (m, 5H), 7.13-7.18 (m, 2H), 7.09-7.10 (m, 1H), 4.35 (s, 3H), 4.14 (s, 3H), 4.11 (s, 3H), 4.10 (s, 3H), 4.05 (s, 3H), 3.77 (s, 3H), 3.60 (s, 3H).

Example 16 Preparation of Compound

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 2′,3′-dimethoxy-5′-(6,7,8-trimethoxy-1-methylisoquinolin-3-yl)phenyl-3′-yltrifluoromethanesulfonate (43 mg, 0.07 mmol), 3-(3-furanyl)phenylboronic acid (12 mg, 0.11 mmol), water/acetonitrile (2 mL/4 ml), K₂CO₃ (24 mg, 0.18 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6 mg, 0.014 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (2.0 mg, 0.07 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100° C. and stirred for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄. The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (20 mg, 54%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.67-7.73 (m, 4H), 7.57 (d, 1H, J=2.04 Hz), 7.36-7.47 (m, 4H), 6.86 (s, 1H), 6.70 (t, 1H, J=0.68 Hz), 3.99 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H), 3.07 (s, 3H).

Example 17 Preparation of Compound

3-(3′-(Furan-3-yl)-5,6-dimethoxy-[1,1′-biphenyl]-3-yl)-6,7,8-trimethoxy-1-methylisoquinoline (15 mg, 0.03 mmol) in iodomethane (1.0 mL) was stirred in a sealed vial at 100° C. for 12 hours. After cooling to room temperature, the solvent was removed. The residue was triturated with EtOAc (5 mL). The solid was collected by filtration and washed with Et₂O to afford the title compound (10 mg, 53%) as light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.77-7.87 (m, 3H), 7.70 (s, 1H), 7.43-7.49 (m, 4H), 7.04-7.08 (m, 2H), 6.74 (s, 1H), 4.31 (s, 3H), 4.10 (s, 3H), 4.07 (s, 2H), 4.06 (s, 3H), 4.02 (s, 3H), 3.71 (s, 3H), 3.56 (s, 3H).

Example 18 Preparation of Compound

A 50-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 2,3-dimethoxy-5-(6,7,8-trimethoxy-1-methylisoquinolin-3-yl)phenyl trifluoromethanesulfonate (200 mg, 0.39 mmol), (4′-fluoro-[1,1′-biphenyl]-3-yl)boronic acid (180 mg, 0.58 mmol), water/acetonitrile (2 mL/6 ml), K₂CO₃ (106 mg, 0.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (20 mg, 0.039 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (5.0 mg, 0.02 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100° C. and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄. The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 10% EtOAc/hexanes afforded the title compound (185 mg, 76%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.58-7.75 (m, 10H), 7.07-7.10 (m, 4H), 6.85 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.65 (s, 3H), 3.07 (s, 3H).

Example 19 Preparation of Compound

A solution of 3-(4″-fluoro-5′-(4-fluorophenyl)-5,6-dimethoxy-[1,1′:3′,1″-terphenyl]-3-yl)-6,7,8-trimethoxy-1-methylisoquinoline in iodomethane (3.0 mL) was stirred in a sealed vial at 100° C. for 2 days. After cooling to room temperature, Et₂O (10 mL) was added to the reaction mixture and the solid was collected by filtration to afford the title compound (156 mg, 73%) as a light yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (m, 2H), 7.76 (m, 2H), 7.73 (m, 1H), 7.66-7.70 (m, 4H), 7.16-7.20 (m, 5H), 7.10 (s, 1H), 4.35 (s, 3H), 4.14 (s, 3H), 4.11 (s, 3H), 4.10 (s, 3H), 4.06 (s, 3H), 3.82 (s, 3H), 3.60 (s, 3H).

Example 20 Preparation of Compound

A 100-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with isoquinolin-3-yl trifluoromethanesulfonate (500 mg, 1.88 mmol), (3-(benzyloxy)-4,5-dimethoxyphenyl)boronic acid (1.1 g, 3.77 mmol), water/acetonitrile (5 mL/20 ml), K₂CO₃ (650 mg, 4.70 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (90 mg, 0.19 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (21 mg, 0.09 mmol) was added and the solution was carefully degassed. The reaction mixture was heated to 100° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with 10% EtOAc/hexanes afforded the title compound (300 mg, 43%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 9.24 (s, 1H), 7.92 (d, 1H, J=8.20 Hz), 7.88 (s, 1H), 7.79 (d, 1H, J=8.24 Hz), 7.61-7.65 (m, 1H), 7.50-7.53 (m, 1H), 7.44-7.46 (m, 2H), 7.31-7.37 (m, 4H), 7.24-7.28 (m, 1H), 5.20 (s, 2H), 3.94 (s, 3H), 3.88 (s, 3H). The requisite intermediate was prepared as follows:

a. Preparation of Compound

A 100-mL round bottom flask equipped with a magnetic stirrer was charged with 3-(3-(benzyloxy)-4,5-dimethoxyphenyl)isoquinoline (300 mg, 0.81 mmol), MeOH (30 mL), and Pd/C (10%, 30 mg). The reaction flask was sealed with septum and purge with N₂ three times; H₂ three times. The reaction mixture was stirred at room temperature under H₂ balloon for 24 hours. TLC showed the starting material was consumed. The reaction mixture was passed through a pad of Celite and washed with MeOH. The filtrate was concentrated to afford the crude title compound (278 mg) as a greenish yellow foam. The crude product was used in next step without further purification and identification.

b. Preparation of Compound

A 100-mL round bottom flask equipped with a magnetic stirrer under nitrogen was charged with 5-(isoquinolin-3-yl)-2,3-dimethoxyphenol (278 mg, 0.99 mmol), CH₂Cl₂ (20 mL), and triethylamine (0.28 ml, 1.98 mmol). After cooling to −70° C., triflic anhydride (0.18 ml, 1.1 mmol) was added via a syringe. The resulting reaction mixture was stirred at −70- TO −30° C. for 30 min. The reaction mixture was diluted with CH₂Cl₂ (30 mL) and washed with saturated NaHCO₃ (10 ml), brine (10 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with CH₂Cl₂ afforded the title compound (150 mg, 37%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.23 (s, 1H), 7.93 (d, 1H, J=8.80 Hz), 7.92 (s, 1H), 7.82 (d, 1H, J=8.20 Hz), 7.73 (d, 1H, J=1.92 Hz), 7.65 (t, 1H, J=7.28 Hz), 7.54 (t, 1H, J=6.92 Hz), 7.50 (d, 1H, J=1.92 Hz), 3.97 (s, 3H), 3.94 (s, 3H).

Example 21 Preparation of Compound

A 25-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 5-(isoquinolin-3-yl)-2,3-dimethoxyphenyl trifluoromethanesulfonate (30 mg, 0.07 mmol), [1,1′-biphenyl]-4-ylboronic acid (20 mg, 0.12 mmol), water/acetonitrile (2 mL/4 ml), K₂CO₃ (21 mg, 0.15 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6 mg, 0.013 mmol). The resulting solution was degassed for S min, then Pd(OAc)₂ (2.0 mg, 0.065 mmol) was added and the solution was carefully degassed. The reaction mixture was warmed to 100° C. and stirred for 1.0 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄. The organic layer was concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (14 mg, 43%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 9.26 (s, 1H), 7.99 (s, 1H), 7.92 (d, 1H, J=8.16 Hz), 7.75-7.79 (m, 3H), 7.42-7.79 (m, 8H), 7.04-7.08 (m, 2H), 4.00 (s, 3H), 3.63 (s, 3H). The requisite intermediate was prepared as follows:

a. Preparation of Compound

A 150-mL round bottom flask equipped with a magnetic stirrer under nitrogen was charged with 6,7-dimethoxy-1-methylisoquinolin-3-ol (1.26 g, 5.8 mmol), CH₂Cl₂ (30 mL), and triethylamine (1.6 ml, 11.5 mmol). After cooling to −70° C., triflic anhydride (1.1 ml, 6.3 mmol) was added via a syringe. The resulting reaction mixture was stirred at −70° C. for 30 min, then room temperature for 1 hour. The reaction mixture was diluted with CH₂Cl₂ (100 mL) and washed with saturated NaHCO₃ (30 ml), brine (30 mL), dried over MgSO₄, and concentrated to afford a crude product as a brown oil. The crude product was purified on silica gel. Elution with CH₂Cl₂ afforded the title compound (1.1 g, 54%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (m, 3H), 4.06 (m, 6H), 2.90 (s, 3H).

Example 22 Preparation of Compound

A solution of 3-(4″-fluoro-5,6-dimethoxy-[1,1′:3′,1″-terphenyl]-3-yl)isoquinoline (14 mg, 0.03 mmol) in iodomethane (1.0 mL) was stirred in a sealed vial at 100° C. for 12 hours. After cooling to room temperature, the solvent was removed and the residue was triturated with EtOAc. The solid was collected by filtration to afford the title compound (10 mg, 55%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 11.0 (s, 1H), 8.78 (d, 1H, J=7.96 Hz), 8.14-8.19 (m, 2H), 8.07-8.09 (m, 1H), 8.00 (t, 1H, J=7.56 Hz), 7.76 (s, 1H), 7.54-7.63 (m, 5H), 7.28-7.32 (m, 1H), 7.13-7.17 (m, 3H), 4.63 (s, 3H), 4.04 (s, 3H), 3.80 (s, 3H).

Example 23 Preparation of Compound

1-(Bromomethyl)-3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinoline (25 mg), acetamidine HCl (7 mg, 1.2 eq.), and K₂CO₃ (17 mg, 2 eq.) in 2 mL DMF were heated at 50° C. for 2 hours. Reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with 10% LiCl solution. Organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 10% MeOH/DCM yielding product as an off-white solid (18 mg, 78% yield). ¹H NMR (400 MHz) (MeOD₄) δ 8.22 (t, J=4 Hz, 1H), 8.13 (s, 1H), 7.94-7.72 (m, 1H), 7.50 (dt, J=8 Hz, J=4 Hz, 1H), 7.46-7.43 (m, 2H), 7.40 (s, 1H), 5.16 (s, 2H), 4.08 (s, 3H), 4.04 (s, 3H), 2.44 (s, 3H), 1.45 (s, 9H). ¹³C NMR (100 MHz) (MeOD₄) δ 167.29, 154.99, 152.81, 152.37, 150.66, 150.11, 140.33, 136.10, 129.60, 126.54, 124.84, 124.61, 122.19, 117.10, 107.30, 103.23, 56.72, 56.60, 46.29, 35.77, 31.92, 19.25. The requisite intermediate was prepared as follows:

a. Preparation of Compound

A 100-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 6,7-dimethoxy-1-methylisoquinolin-3-yl trifluoromethanesulfonate (700 mg, 1.99 mmol), (3-(tert-butyl)phenyl)boronic acid (426 mg, 2.39 mmol), water/acetonitrile (5 mL/15 ml), K₂CO₃ (550 mg, 3.99 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (95 mg, 0.20 mmol). The resulting solution was degassed for 5 min, then Pd(OAc)₂ (22.4 mg, 0.10 mmol) was added and the reaction mixture was carefully degassed. The reaction mixture was heated to 100° C. and stirred for 1 hour. The reaction mixture was warmed to 100° C. and stirred for 1 hour. After cooling to 20° C., the reaction mixture was diluted with EtOAc (100 mL) and washed with saturated NaHCO₃ (30 mL), brine (30 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (600 mg, 90%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.13 (m, 1H), 7.85-7.93 (m, 1H), 7.76 (s, 1H), 7.41-7.46 (m, 2H), 7.32 (s, 1H), 7.16 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.00 (s, 3H), 1.44 (s, 9H).

b. Preparation of Compound

3-(3-(tert-Butyl)phenyl)-6,7-dimethoxy-1-methylisoquinoline (400 mg), NBS (223 mg, 1.05 eq.), and AIBN (20 mg, 0.1 eq.) in 7 mL CCl₄ were heated at 85° C. for 2 hours. Reaction mixture was then cooled to room temperature and diluted with hexane. Solid precipitate was filtered off and filtrate was concentrated. Chromatography achieved using ISCO max gradient 15% EtOAc/hexane yielding product as a white solid (350 mg, 71% yield). ¹H NMR (400 MHz) (CDCl₃) δ 8.15-8.14 (m, 1H), 7.94-7.91 (m, 2H), 7.48-7.45 (m, 3H), 7.18 9s, 1H), 5.10 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 1.45 (s, 9H). ¹³C NMR (100 MHz) (CDCl₃) δ 153.03, 152.89, 151.50, 150.11, 149.96, 139.19, 134.59, 128.46, 125.45, 124.18, 123.86, 121.45, 116.56, 105.75, 103.56, 56.16, 56.10, 34.90, 32.97, 31.47.

Example 24 Alternative Preparation of the Compound of Example 13

A 20-mL vial was added methyl di-tert-butyl ((((3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-1-yl)methyl)amino)methylene)dicarbamate (300 mg, 0.50 mmol), CH₂Cl₂ (3 mL), and TFA (3 mL). The sealed vial was stirred at 50° C. for 1 hour. The solvent was removed and the residue was purified on silica gel. Elution with CH₂Cl₂ to (10/89/1: MeOH/CHCl₃/ammonium hydroxide) afforded the title compound (163 mg, 82%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.84 (t, 1H, J=5.84 Hz), 8.00 (s, 1H), 7.93 (s, 1H), 7.77-7.79 (m, 1H), 7.41-7.48 (m, 3H), 7.18 (s, 1H), 4.86 (d, 1H, J=5.76 Hz), 4.11 (s, 3H), 4.07 (s, 3H), 1.68 (broad s, 2H), 1.41 (s, 9H).

a. Preparation of Compound

A 50-mL round bottom flask equipped with a magnetic stirrer, a condenser and a nitrogen in/outlet adapter was charged with 3-(3-(tert-butyl)phenyl)-6,7-dimethoxy-1-bromomethylisoquinoline (400 mg, 0.97 mmol), DMF (3 mL), K₂CO₃ (266 mg, 1.93 mmol), and 1,3-bis(tert-butoxycarbonyl)guanidine (300 mg, 1.16 mmol) The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL), 10% LiCl (30 mL), brine (30 mL), dried over Na₂SO₄, concentrated in rotavapor and purified on silica gel. Elution with 20% EtOAc/hexanes afforded the title compound (325 mg, 57%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.54 (broad s, 2H), 8.18 (s, 1H), 7.66-7.70 (m, 2H), 7.17-7.19 (m, 2H), 5.64 (s, 2H), 3.86 (s, 6H), 1.24 (s, 9H), 1.21 (s, 9H), 0.87 (s, 9H).

Example 25

The following can illustrate representative pharmaceutical dosage forms, containing a compound of formula I (‘Compound X’), for therapeutic or prophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 01N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. 

What is claimed is:
 1. A compound of formula I:

wherein: the bond represented by - - - is a double bond, R¹⁰ is absent, and W is (NR³⁰)⁺D⁻; R¹ is —NR^(3a)R^(3b), —C(═NR^(3cb))—NR^(3cc)R^(3cd), aryloxy, cyano, or (C₁-C₆)alkyl that is substituted with one or more —NR3^(ce−)C(═NR^(3cb))R^(3ce), —C(═NR^(3cb))—NR^(3cc)R^(3cd), —NR^(3ce)—C(═NR^(3cb))—NR^(3cc)R^(3cd), and —NR^(3ce)—C(═O)—NR^(3cc)R^(3cd); at least one of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is aryl or heteroaryl; and the remainder of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is selected from hydrogen, halo, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, hetero aryl (C₁-C₆)alkyl, aryl (C₁-C₆)alkanoyl, and heteroaryl (C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); any adjacent R⁶, R⁷, R⁸, R^(4′) and R^(5′) taken together can optionally be methylenedioxy and each remaining R⁶, R⁷, R⁸, R^(4′) and R^(5′) is independently selected from H, R^(3bb), and Z—R^(3x); each Z is independently selected from —O—, —S—, and —N(R^(3y))—; R³⁰ is absent and D⁻ is absent; or R³⁰ is H or (C₁-C₆)alkyl and D⁻ is counterion; A is N or C—R^(4′); R^(3a) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, —NR^(3da)R^(3db), and aryloxy, and wherein each aryl and heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; and R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═NR^(3cb))—NR^(3cc)R^(3cd), —C(═NR^(3cb))— R^(3ea), —C(═O)—R^(3m), —C(═O)—OR^(3n), —C(═O)—SR^(3p), —C(═O)—NR^(3q)R^(3r), —C(═S)—R^(3m), —C(═S)—OR^(3n), —C(═S)—SR^(3p), or —C(═S)—NR^(3q)R^(3r); wherein each (C₁-C₆)alkyl of R^(3b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, —NR^(3da)R^(3db), and aryloxy; and wherein each aryl, and heteroaryl of R^(b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, and aryloxy; or R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino, pyrrole, indole, or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino pyrrole, indole, or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl; R^(3c) is hydrogen, (C₁-C₆)alkyl, aryl, or heteroaryl; R^(3d) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(3e)R^(3f); R^(3e) and R^(3f) are each independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3e) and R^(3f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3g) and R^(3h) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3g) and R^(3h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3j) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3k) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3m) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3n) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); each R^(3p) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl, wherein each aryl, and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); each R^(3q) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(3r) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3q) and R^(3r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3u) and R^(3v) is independently selected from H and (C₁-C₆)alkyl; each R^(3x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(3u)R^(3v); each R^(3y) is independently selected from H and (C₁-C₆)alkyl; each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3bb) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); each R^(3cb) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3cc) and R^(3cd) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3cc) and R^(3cd) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(3cc) and R^(3cd) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(3cm)R^(3cn); each R^(3ce) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3cg) and R^(3ch) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3cg) and R^(3ch) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; wherein any (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl or heteroaryl(C₁-C₆)alkyl of R^(3cg) and R^(3ch) is optionally substituted with one or more groups independently selected from hydroxy, carboxy, and NR^(3cm)R^(3cn); each R^(3cm) and R^(3cn) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(cm) and R^(cn) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3da) and R^(3db) is independently selected from H, (C₁-C₆)alkyl, cycloalkyl, cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3da) and R^(3db) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; and R^(ea) is H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, or (C₁-C₆)alkanoyl; or a salt thereof.
 2. The compound of claim 1 which is:

or a salt thereof.
 3. The compound of claim 1 which is:

or a salt thereof.
 4. The compound of claim 1 wherein: the bond represented by - - - is present, R¹⁰ is absent, and W is (NR³⁰)⁺D⁻; R⁶ R⁷, R⁸, R^(4′) and R^(5′) are each independently selected from H and Z—R^(x); or R⁶and R⁷ taken together are methylenedioxy and R⁸, R^(4′), and R^(5′) are each independently selected from H and Z—R^(x); or R⁷ and R⁸ taken together are methylenedioxy and R⁶ R^(4′) and R^(5′) are each independently selected from H and Z—R^(x); or R^(4′) and R^(5′) taken together are methylenedioxy and R⁶ R⁷, and R⁸ are each independently selected from H and —Z—R^(x); each Z is independently selected from —O—, —S—, and —N(R^(y))—; at least one of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is aryl or heteroaryl; and the remainder of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is selected from hydrogen, hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, aryl(C₁-C₆)alkanoyl, and heteroaryl(C₁-C₆)alkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, and (C₁-C₆)alkanoyl of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); R³⁰ is absent and X⁻ is absent; or R³⁰ is H or (C₁-C₆)alkyl and X⁻ is counterion; R¹¹ is —NR^(3a)R^(3b) or cyano; R^(3a) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, or heteroaryl(C₁-C₆)alkyl; wherein each (C₁-C₆)alkyl of R^(3a) is optionally substituted with one or more groups selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy, and wherein each aryl and heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; and R^(3b) is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl, heteroaryl(C₁-C₆)alkyl, —C(═O)—R^(3m), —C(═O)—OR^(3n), —C(═O)—S3p^(p), —C(═O)—NR^(3q)R^(3r), —C(═S)—R^(3m), —C(═S)—OR^(3n), —C(═S)—SR^(3p), —C(═S)—NR^(3q)R^(3r), or —C(═NR^(3c))—R^(3d); wherein each (C₁-C₆)alkyl of R^(3b) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, oxo, carboxy, and aryloxy; and wherein each aryl, and heteroaryl of R^(3b) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, carboxy, and aryloxy; or R^(3a) and R^(3b) taken together with the nitrogen to which they are attached form aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino, which aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino can optionally be substituted with one or more (C₁-C₆)alkyl; R^(3c) is hydrogen, (C₁-C₆)alkyl, aryl, or heteroaryl; R^(3d) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyl, or —NR^(3e)R^(3f); R^(3e) and R^(3f) are each independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(e) and R^(f) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3g) and R^(3h) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆) alkyl; or R^(3g) and R^(3h) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3j) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3k) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3m) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3n) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3p) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; each R^(3q) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; and each R^(3r) is independently selected from H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, heteroaryl, aryl(C₁-C₆) alkyl and heteroaryl(C₁-C₆)alkyl; or R^(3q) and R^(3r) together with the nitrogen to which they are attached form a aziridino, azetidino, morpholino, piperazino, pyrrolidino or piperidino; each R^(3u) and R^(3v) is independently selected from H and (C₁-C₆)alkyl; each R^(3x) is independently selected from (C₁-C₆)alkyl, (C₁-C₆)alkanoyl, and —C(═O)NR^(3u)R^(3v); and each R^(3y) is independently selected from H and (C₁-C₆)alkyl; or a salt thereof.
 5. The compound of claim 1 which is a compound of formula (IIIa):

wherein R^(6′) is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R^(6′) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R^(6′) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt thereof.
 6. The compound of claim 1 which is a compound of formula (IIIb):

wherein R^(3′) is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R^(3′) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R^(3′) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt thereof.
 7. The compound of claim 1 which is a compound of formula (IIIc):

wherein R^(2′) is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R^(2′) is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂Rv^(k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R^(2′) is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt thereof.
 8. The compound of claim 1 which is a compound of formula (IIId):

wherein R⁴ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁴ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁴ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt thereof.
 9. The compound of claim 1 which is a compound of formula (IIIe):

wherein R⁵ is selected from hydroxy, carboxy, cyano, CF₃SO₃—, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, aryl(C₁-C₆)alkyl, aryl, heteroaryl, heteroaryl(C₁-C₆)alkyl, arylalkanoyl, and heteroarylalkanoyl; wherein each (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, cycloalkyl, and (C₁-C₆)alkanoyl of R⁵ is optionally substituted with one or more groups independently selected from halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, oxo, carboxy, aryloxy, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and wherein each aryl, and heteroaryl of R⁵ is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); or a salt thereof.
 10. The compound of claim 1 wherein R⁶, R⁷, R⁸, R^(4′) and R^(5′) are each independently (C₁-C₃)alkoxy.
 11. The compound of claim 1 wherein R⁶, R⁷, R⁸, R^(4′) and R^(5′) are each methoxy.
 12. The compound of claim 1 wherein R⁷, R⁸, R^(4′) and R^(5′) are each methoxy.
 13. The compound of claim 1 wherein R^(6′) is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)Rv^(h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)Rv^(h).
 14. The compound of claim 1 wherein R^(3′) is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).
 15. The compound of claim 1 wherein R^(2′) is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g3)R^(h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).
 16. The compound of claim 1 wherein R⁴ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).
 17. The compound of claim 1 wherein R⁵ is selected from phenyl, pyridyl and furanyl and is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, R^(3aa), —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h); and each R^(3aa) is independently selected from aryl and heteroaryl, which aryl and heteroaryl is optionally substituted with one or more groups independently selected from (C₁-C₆)alkyl, halo, hydroxy, cyano, nitro, (C₁-C₆)alkoxy, cycloalkyl, carboxy, aryloxy, nitro, sulfo, —S(O)₂NR^(3g)R^(3h), —N(R^(3j))S(O)₂R^(3k), and —NR^(3g)R^(3h).
 18. The compound of claim 1 wherein at least one of R⁴, R⁵, R^(2′), R^(3′), and R^(6′) is selected from 3-biphenyl, 3-(4′-fluoro)biphenyl, 4-biphenyl, 4-(4′-fluoro)biphenyl, 3,5-bis(4-fluorophenyl)phenyl, 4-fluorophenyl, phenyl, 3-pyridyl, 4-pyridyl, 3-dimethylaminophenyl, 3-furanyl, 3-methoxyphenyl, 4-pyrid-3-ylphenyl, 4-pyrid-4-ylphenyl, 4-(3-dimethylaminophenyl)phenyl, 4-(3-furanyl)phenyl, 2-phenylpyrid-4-yl, 2-(3-methoxyphenyl)pyrid-3-yl, 2-phenylfur-4-yl, and 2-pyrid-4-yl)pyrid-5-yl.
 19. A composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.
 20. A method for inhibiting FtsZ polymerization in a bacterium comprising contacting the bacterium with an amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, effective to inhibit FtsZ polymerization.
 21. A method for inhibiting FtsZ Z-ring formation in a bacterium comprising contacting the bacterium with an amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, effective to inhibit FtsZ Z-ring formation.
 22. A method for inhibiting the recruitment of divisome proteins in a bacterium comprising contacting the bacterium with an amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, effective to inhibit the recruitment of divisome proteins.
 23. A method for treating a bacterial infection in a mammal comprising administering to the mammal an effective amount of a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof.
 24. The method of claim 23 wherein the bacterial infection is a Gram-negative bacterial strain infection.
 25. The method of claim 23 wherein the bacterial infection is a Gram-positive bacterial strain infection.
 26. The method of claim 23 wherein the bacterial infection is a multiple drug-resistant bacterial strain infection.
 27. The method of claim 26 wherein the multiple drug-resistance bacterial strain is selected from the group consisting of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, multiple drug-resistant tuberculosis and multidrug-resistant Clostridium difficile. 